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Maître de Conférences, Habilité(e) à Diriger des Recherches
Faculté des Sciences et Technologies - Nancy
Université de Lorraine
+33 (0)3 72 74 56 52 | henri.schroeder@univ-lorraine.fr
Toxics, 10 (4), pp. 180.
Morel, C., Christophe, A., Maguin Gaté, K., Paoli, J., Turner, J.D., Schroeder, H., Grova, N.
Archives of Toxicology, 95 (9), pp. 3085-3099.
Bernal Melendez, E., Callebert, J., Bouillaud-Kremarik, P., Persuy, M.-A., Olivier, B., Badonnel, K., Chavatte-Palmer, P., Baly, C., Schroeder, H.
Limited studies in humans and in animal models have investigated the neurotoxic risks related to a gestational exposure to diesel exhaust particles (DEP) on the embryonic brain, especially those regarding monoaminergic systems linked to neurocognitive disorders. We previously showed that exposure to DEP alters monoaminergic neurotransmission in fetal olfactory bulbs and modifies tissue morphology along with behavioral consequences at birth in a rabbit model. Given the anatomical and functional connections between olfactory and central brain structures, we further characterized their impacts in brain regions associated with monoaminergic neurotransmission. At gestational day 28 (GD28), fetal rabbit brains were collected from dams exposed by nose-only to either a clean air or filtered DEP for 2 h/day, 5 days/week, from GD3 to GD27. HPLC dosage and histochemical analyses of the main monoaminergic systems, i.e., dopamine (DA), noradrenaline (NA), and serotonin (5-HT) and their metabolites were conducted in microdissected fetal brain regions. DEP exposure increased the level of DA and decreased the dopaminergic metabolites ratios in the prefrontal cortex (PFC), together with sex-specific alterations in the hippocampus (Hp). In addition, HVA level was increased in the temporal cortex (TCx). Serotonin and 5-HIAA levels were decreased in the fetal Hp. However, DEP exposure did not significantly modify NA levels, tyrosine hydroxylase, tryptophan hydroxylase or AChE enzymatic activity in fetal brain. Exposure to DEP during fetal life results in dopaminergic and serotonergic changes in critical brain regions that might lead to detrimental potential short-term neural disturbances as precursors of long-term neurocognitive consequences.
Frontiers in Genetics Epigenomics and Epigenetics, 657171 (1), pp. 1-13.
Fernandes, S.B., Grova, N., Roth, S., Duca, R.D., Godderis, L., Guebels, P., Mérieux, S., Lumley, A.I., Bouillaud-Kremarik, P., Ernens, I., Devaux, Y., Schroeder, H., Turner, J.D.
DNA methylation is one of the most important epigenetic modifications and is closely related with several biological processes such as regulation of gene transcription and the development of non-malignant diseases. The prevailing dogma states that DNA methylation in eukaryotes occurs essentially through 5-methylcytosine but recently adenine methylation was also found to be present in eukaryotes. In mouse embryonic stem cells, 6-methyladenine was associated with the repression and silencing of genes, particularly in the X-chromosome, known to play an important role in cell fate determination. Here, we have demonstrated that 6mA is a ubiquitous eukaryotic epigenetic modification that is put in place during epigenetically sensitive periods such as embryogenesis and foetal development. In somatic cells there are clear tissue specificity in 6mA levels, with the highest 6mA levels being observed in the brain. In zebrafish, during the first 120h of embryo development, from a single pluripotent cell to an almost fully formed individual, 6mA levels steadily increase. An identical pattern was observed over embryonic days 7-21 in the mouse. Furthermore, exposure to a neurotoxic environmental pollutant during the same early life period may led to a decrease in the levels of this modification in female rats. The identification of the periods during which 6mA epigenetic marks are put in place increases our understanding of this mammalian epigenetic modification, and raises the possibility that it may be associated with developmental processes.
Toxics, 9 (50), pp. 1-18.
Saber Cherif, L., Cao-Lei, L., Farinelle, S., Muller, C.P., Turner, J.T., Schroeder, H., Grova, N.
The potent neurotoxicity of benzo[a]pyrene (B[a]P) has been suggested to be a susceptibility factor accelerating the onset of brain tumours and the emergence of neurobehavioural disturbances. B[a]P has been shown to be neurotoxic, acting directly on both the central and peripheral nervous systems, as well as indirectly via peripheral organs like liver and gut. By using a realistic B[a]P exposure scenario (0.02–200 mg/kg/day, 10 days) in mice, we elucidated brain-specific B[a]P metabolism and at identified hydroxylated B[a]P metabolites in serum which could be used as markers of cognitive impairment. Repeated oral administration of B[a]P led to, at the doses of 20 and 200 mg/kg/day, significant overexpression of Cyp1a1/Cyp1b1 in 2 out of the 3 brain regions considered, thereby suggesting the ability of the brain to metabolize B[a]P itself. At the same doses, mice exhibited a reduction in anxiety in both the elevated plus maze and the hole board apparatus. Concomitantly, B[a]P triggered dose-dependent changes in Nmda subunit expression (Nr1 and Nr2a/Nr2b) in areas involved in cognition. We detected 9-OH-B[a]P and 7,8-diol-B[a]P in serum at the level for which cognitive impairment was observed. We suggest that these metabolites may, in the future be exploited as potent biomarkers of B[a]P-induced cognitive impairments.
Particle and Fibre Toxicology, 16 (1), pp. 1-17.
Bernal Melendez, E., Lacroix, M.C., Bouillaud-Kremarik, P., Callebert, J., Olivier, B., Persuy, M.A., Durieux, D., Rousseau-Ralliard, D., Aioun, J., Cassee, F., Couturier-Tarrade, A., Valentino, S., Chavatte-Palmer, P., Schroeder, H., Baly, C.
Background: Airborne pollution, especially from diesel exhaust (DE), is known to have a negative effect on the central nervous system in exposed human populations. However, the consequences of gestational exposure to DE on the fetal brain remain poorly explored, with various effects depending on the conditions of exposure, as well as little information on early developmental stages. We investigated the short-term effects of indirect DE exposure throughout gestation on the developing brain using a rabbit model. We analyzed fetal olfactory tissues at the end of gestation and tested behaviors relevant to pups’ survival at birth. Pregnant dams were exposed by nose-only inhalation to either clean air or DE with a content of particles (DEP) adjusted to 1 mg/m3 by diluting engine exhaust, for 2 h/day, 5 days/week, from gestational day 3 (GD3) to day 27 (GD27). At GD28, fetal olfactory mucosa, olfactory bulbs and whole brains were collected for anatomical and neurochemical measurements. At postnatal day 2 (PND2), pups born from another group of exposed or control
female were examined for their odor-guided behavior in response to the presentation of the rabbit mammary pheromone 2-methyl-3-butyn-2-ol (2MB2).
Results: At GD28, nano-sized particles were observed in cilia and cytoplasm of the olfactory sensory neurons in the olfactory mucosa and in the cytoplasm of periglomerular cells in the olfactory bulbs of exposed fetuses. Moreover, cellular and axonal hypertrophies were observed throughout olfactory tissues. Concomitantly, fetal serotoninergic and dopaminergic systems were affected in the olfactory bulbs. Moreover, the neuromodulatory homeostasis was disturbed in a sex-dependent manner in olfactory tissues. At birth, the olfactory sensitivity to 2MB2 was reduced in exposed PND2 pups.
Conclusion: Gestational exposure to DE alters olfactory tissues and affects monoaminergic neurotransmission in fetuses’ olfactory bulbs, resulting in an alteration of olfactory-based behaviors at birth. Considering the anatomical and functional continuum between the olfactory system and other brain structures, and due to the importance of monoamine neurotransmission in the plasticity of neural circuits, such alterations could participate to disturbances in higher integrative structures, with possible long-term neurobehavioral consequences.
EFSA Technical Report, doi:10.2903/sp.efsa.2019.EN-1732
Croera, C., Baltke, M., Corsini, E., Fitzgerald, R.E., Gott, D., Ntzani, E., Gundert-remy, U., Halldorsson, T., Schroeder, H., Scanziani, E., Steffensen, I.L., Ulbrich, B., Waalkens-berendsen, I., WÖlfle, D., Barizzone, F., Barucci, F., Van haver, E., Castoldi, A.F., Van loveren, H.
Prior to being applied to the new bisphenol A (BPA) re-evaluation, the study appraisal methodology described in the 2017 BPA hazard assessment protocol, i.e. the so-called ‘2017 methodology’, was tested on a selection of studies that had been previously appraised by EFSA in the context of its 2015 and 2016 assessments of BPA. This report describes this testing phase, its outcome and the resulting refinement of the 2017 methodology. The goals of this testing phase were to i) test the functioning of the 2017 internal validity appraisal tools for human and animal studies, and specifically (a) to verify whether the final tier of internal validity (on a three-tier scale, with Tier 1 being the highest) automatically assigned to each study on the basis of pre-defined criteria after answering the questions of the risk of bias tool reflected the internal validity according to expert judgement and (b) to fine-tune and calibrate the 2017 appraisal tool on a sufficiently large study sample (development of the ‘2019 methodology’); ii) assess the comparability of the study appraisal outcome by the 2019 methodology against the ‘2015 methodology’ applied in the EFSA BPA assessments of 2015 and 2016. Concerning the first goal, the automatic allocation of epidemiological studies to an internal validity tier, based on pre-defined criteria for combining the appraisal questions’ scores, resulted in ranking them exclusively in Tier 3 (the lowest tier), in full accordance with expert judgment. For animal studies, to enable discrimination of studies into three tiers, the appraisal tool was refined; thereafter, comparability between automatic allocation-based and expert judgement-based scoring reached 91% (43 out of 47 appraisals). Concerning the second goal, it is acknowledged that the 2015 and 2019 methodologies present some differences with respect to the elements considered for assessing the study quality (i.e. reliability vs. internal validity). Nonetheless, the key study used to derive BPA’s tolerable daily intake in the 2015 Opinion was also considered to be of high quality according to the 2019 methodology. In addition, the outcome of the appraisal of the papers by the 2019 methodology versus the 2015 methodology was overall comparable or more stringent in 92% of the cases (24 out of 26 appraisals). It follows that despite some intrinsic differences, the 2015 methodology previously used by EFSA to appraise the BPA evidence is considered sufficiently robust, even though not as structured as the 2019 methodology. Overall, the two goals of the testing phase have been achieved. The amendments of the appraisal methodology are being implemented for the full re-evaluation of the new BPA literature and will be fully documented in the final version of the protocol annexed to the new BPA Opinion.
International Journal of Genomics, doi.org/10.1155/2019/2085496
Grova, N., Schroeder, H., Olivier, J.-L., Tuner, J.D.
The incidence of neurodevelopmental and neurodegenerative diseases worldwide has dramatically increased over the last decades. Although the aetiology remains uncertain, evidence is now growing that exposure to persistent organic pollutants during sensitive neurodevelopmental periods such as early life may be a strong risk factor, predisposing the individual to disease development later in life. Epidemiological studies have associated environmentally persistent organic pollutant exposure to brain disorders including neuropathies, cognitive, motor, and sensory impairments; neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD); and neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). In many ways, this expands the classical “Developmental Origins of Health and Disease” paradigm to include exposure to pollutants. This model has been refined over the years to give the current “three-hit” model that considers the individual’s genetic factors as a first “hit.” It has an immediate interaction with the early-life exposome (including persistent organic pollutants) that can be considered to be a second “hit.” Together, these first two “hits” produce a quiescent or latent phenotype, most probably encoded in the epigenome, which has become susceptible to a third environmental “hit” in later life. It is only after the third “hit” that the increased risk of disease symptoms is crystallised. However, if the individual is exposed to a different environment in later life, they would be expected to remain healthy. In this review, we examine the effect of exposure to persistent organic pollutants and particulate matters in early life and the relationship to subsequent neurodevelopmental and neurodegenerative disorders. The roles of those environmental factors which may affect epigenetic DNA methylation and therefore influence normal neurodevelopment are then evaluated.
Molecular and Cellular Endocrinology, 475, pp. 92-106.
Antignac, J.P., Applanat, M., Appenzeller, B.M.R., Beaudouin, R., Belzunces, L.P., Canivenc-lavier, M.C., Chevalier, A., Chevrier, C., Cravedi, J.P., Elefant, E., Emond, C., Eustache, F., Habert, R., Kolf-clauw, M., Le magueresse-battistoni, B., Mhaouty-kodja, S., Minier, C., Multignier, L., Schroeder, H., Thonneau, P., Pviguie, C., Pouzaud, F., Thierry-mieg, M., Burga, K., Verines-join, L., Fiore, K., Beausoleil, C., Michel, C., Rousselle, C., Pasquier, E.
The extensive database on BPA provides strong evidence of its adverse effects on reproductive, neurobehavioural, metabolic functions and mammary gland. Disruption of estrogenic pathway is central in the mediation of these effects although other modes of action may be involved. BPA has a weak affinity for ERα/β but interaction with extranuclearly located pathways activated by estrogens such as ERRγ and GPER reveals how BPA can act at low doses.
The effects are observed later in life after developmental exposure and are associated with pathologies of major societal concern in terms of severity, incidence, impact on quality of life, burden on public health system. The complexity of the dose response raise uncertainties on the possibility to establish safe levels and the scope of ED-mediated effects of BPA may be wider. These concerns fulfill the requirements for ED identification under REACH regulation.
Molecular and Cellular Endocrinology, 475, pp. 4-9.
Beausoleil, C., Emond, C., Cravedi, J.P., Antignac, J.P., Applanat, M., Appenzeller, B.M.R., Beaudouin, R., Belzunces, L.P., Canivenc, M.C., Chevalier, A., Chevrier, C., Elefant, E., Eustache, F., Habert, R., Kolf-clauw, M., Le magueresse-battistoni, B., Mhaouty-kodja, S., Minier, C., Multignier, L., Schroeder, H., Thonneau, P., Viguie, C., Pouzaud, F., Ormsby, J.N., Rousselle, C., Verines-jouin, L., Pasquier, E., Michel, C.
BPA is one of the most investigated substances for its endocrine disruptor (ED) properties and it is at the same time in the center of many ED-related controversies. The analysis on how BPA fits to the regulatory identification as an ED is a challenge in terms of methodology. It is also a great opportunity to test the regulatory framework with a uniquely data-rich substance and learn valuable lessons for future cases. From this extensive database, it was considered important to engage in a detailed analysis so as to provide specific and strong evidences of ED while reflecting accurately the complexity of the response as well the multiplicity of adverse effects. An appropriate delineation of the scope of the analysis was therefore critical. Four effects namely, alterations of estrous cyclicity, mammary gland development, brain development and memory function, and metabolism, were considered to provide solid evidence of ED-mediated effects of BPA.
Molecular and Cellular Endocrinology, 475, pp. 54-73.
Mhaouty-Kodja, S., Belzunces, L.P., Canivenc, M.C., Schroeder, H., Chevrier, C., Pasquier, E.
Many rodent studies and a few non-human primate data report impairments of spatial and non-spatial memory induced by exposure to bisphenol A (BPA), which are associated with neural modifications, particularly in processes involved in synaptic plasticity. BPA-induced alterations involve disruption of the estrogenic pathway as established by reversal of BPA-induced effects with estrogenic receptor antagonist or by interference of BPA with administered estradiol in ovariectomized animals. Sex differences in hormonal impregnation during critical periods of development and their influence on maturation of learning and memory processes may explain the sexual dimorphism observed in BPA-induced effects in some studies. Altogether, these data highly support the plausibility that alteration of learning and memory and synaptic plasticity by BPA is essentially mediated by disturbance of the estrogenic pathways. As memory function in humans involves similar signaling pathways, this mode of action of BPA has the potential to alter human cognitive abilities.
Archives of Toxicology, 91 (8), pp. 2813-2825.
Appenzeller, B.M.R., Hardy, E.M., Grova, N., Chata, C., Fays, F., Briand, O., Schroeder, H., Duca, R.C.
Urine and plasma have been used to date for the biomonitoring of exposure to pollutants and are still the preferred fluids for this purpose; however, these fluids mainly provide information on the short term and may present a high level of variability regarding pesticide concentrations, especially for nonpersistent compounds. Hair analysis may provide information about chronic exposure that is averaged over several months; therefore, this method has been proposed as an alternative to solely relying on these fluids. Although the possibility of detecting pesticides in hair has been demonstrated over the past few years, the unknown linkage between exposure and pesticides concentration in hair has limited the recognition of this matrix as a relevant tool for assessing human exposure. Based on a rat model in which there was controlled exposure to a mixture of pesticides composed of lindane, β-hexachlorocyclohexane, β-endosulfan, p,p′-DDT, p,p′-DDE, dieldrin, pentachlorophenol, diazinon, chlorpyrifos, cyhalothrin, permethrin, cypermethrin, propiconazole, fipronil, oxadiazon, diflufenican, trifluralin, carbofuran, and propoxur, the current work demonstrates the association between exposure intensity and resulting pesticide concentration in hair. We also compared the results obtained from a hair analysis to urine and plasma collected from the same rats. Hair, blood, and urine were collected from rats submitted to 90-day exposure by gavage to the aforementioned mixture of common pesticides at different levels. We observed a linear relationship between exposure intensity and the concentration of pesticides in the rats’ hair (R Pearson 0.453–0.978, p < 0.01). A comparison with results from urine and plasma samples demonstrated the relevance of hair analysis and, for many chemicals, its superiority over using fluids for differentiating animals from different groups and for re-attributing animals to their correct groups of exposure based on pesticide concentrations in the matrix. Therefore, this study strongly supports hair analysis as a reliable tool to be used during epidemiological studies to investigate exposure-associated adverse health effects.
Neurotoxicology, 53, pp. 321-333.
Peiffer, J., Grova, N., Hidalgo, S., Salquèbre, G., Rychen, G., Bisson, J.-F., Appenzeller, B.M., Schroeder, H.
Neurotoxicology & Teratology, 52 (Part B), pp. 170-180.
Maurice, N., Olry, J.-C., Cariou, R., Dervilly-Pinel, G., Le Bizec, B., Travel, A., Jondreville, C., Schroeder, H.
Neurotoxicology, 43 (1), pp. 90-101.
Crepeaux, G., Grova, N., Bouillaud-Kremarik, P., Sikahyeva, N., Salquebre, G., Rychen, G., Soulimani, R., Appenzeller, B.M., Schroeder, H.
J. Chromatogr. A, 1364 (1), pp. 183-191.
Grova, N., Salquebre, G., Hardy, E., Schroeder, H., Appenzeller, B.M.
Food and Chemical Toxicology, 56, pp. 371-380.
Chahin, A., Peiffer, A., Olry, J-C., Crepeaux, G., Schroeder, H., Rychen, G., Guiavarc’h, Y.
Little is known in terms of multi-matrix cytochrome P450 activity induction under repeated oral exposure
to planar halogenated and polycyclic aromatic hydrocarbons (PHH, PAH). In the present study, 60
rats were daily exposed, during 28 days, to oral ingestion of a mixture consisting of phenanthrene, pyrene
and benzo(a)pyrene at 0, 6 or 600 lg/day. EROD activity, reflecting almost exclusively CYP1A1 and
CYP1B1 activities, was measured in brain and liver microsomes as well as in peripheral blood lymphocytes
(PBLs). All induction kinetics could be appropriately fitted using logistic-like models. After 28 days
of exposure to a 6 lg/day dose, EROD activity was found to be 91, 152 and 94-fold increased in lymphocytes,
liver and brain, respectively, compared to day 0. Plateau activities could be appropriately fitted versus
ingested doses using Hill or Michaelis–Menten models. Correlations between matrices made it
possible to conclude that EROD activity in PBL should be considered as a sensitive, convenient and
non-destructive approach for (i) evaluating EROD activity in liver, which was found to represent 98%
of the observed EROD activities in the three tested matrices and (ii) evaluating oral exposure of homogeneous
groups of farm animals (race, diet) to CYP inducing PAH and PHH.
Toxicology Letters, 221 (1), pp. 40-46.
Crepeaux, G., Bouillaud-Kremarik, P., Sikhayeva, N., Rychen, G., Soulimani, R., Schroeder, H.
Polycyclic aromatic hydrocarbons (PAHs) are persistent organic pollutants originating from incompletecombustion processes. Humans are mainly exposed through contaminated food ingestion. PAHs are neu-rotoxic compounds both for human and rodents, and may be found in placenta, umbilical cord blood andbreast milk, suggesting that early exposure may impact developing central nervous system.In a previous study we showed that PAH exposure during both gestation and lactation periods in ratsincreased anxiety-related behaviours and decreased cerebral metabolism in several key structures linkedto the limbic system on male pups at the adult stage. The aim of the present study was to assess the effectsof an exclusive gestational PAH exposure on the same aspects of brain functionality. Female rats wereexposed through diet to a 16 PAH mixture at doses of 2 g/kg/day or 200 g/kg/day during gestation.Late neurotoxic effects were evaluated by carrying out behavioural and cognitive tests and histochemicalanalyses using cytochrome oxidase activity as a cerebral metabolism marker in different brain areas.The results of this study revealed that behaviour and cerebral metabolism on prenatally PAH exposedadult rats was not significantly affected by the exposure to these pollutants. Finally this work highlights that the exposure period to pollutants such as PAHs at very early stages ofdevelopment play a key role on the neurological impairment induced.
Neurotoxicology, 38, pp. 74-83.
Domange, C., Schroeder, H., Violle, N., Peiffer, J., Canlet, C., Paris, A., Priymenko, N.
C57BL/6J mice orally exposed to 9% H. radicata (HR) are metabolically competent laboratory animals which can be used as model of Australian stringhalt, a neurological horse disease induced by HR ingestion. So, the present study was conducted to assess the brain metabolome and the behavioural performances of mice fed with a 9%-HR-based diet for 21 days. By the end of the period of exposure, mice were investigated for motor activity and coordination, anxiety level, learning and memory performances, social behaviour and rewarding properties of for the plant. Thus, the animals were sacrificed and the brain metabolome was studied using 1H NMR spectroscopy. HR-exposed mice displayed a motor hyperactivity in several tasks, a less resignation in the forced swimming test, and paradigm place preference for the plant. A bootstrap-based regularized canonical analysis performed on merged behavioural and metabolic datasets showed a clear relationship in HR-treated mice between an increase in cerebral scyllo-inositol, an increased motor activity, and seemingly rewarding properties of HR. These results underlie the interest of such a dual approach to characterize functional end-points of a pathophysiological model of the Australian stringhalt in equine species.
PlosOne, 8 (8), e71713.
Peiffer, J., Cosnier, F., Grova, N., Nunge, H., Salquebre, G., Decret, M.J., Cossec, B., Rychen, G., Appenzeller, B.M., Schroeder, H.
Fluorene is one of the most abundant polycyclic aromatic hydrocarbons in air and may contribute to the neurobehavioral alterations induced by the environmental exposure of humans to PAHs. Since no data are available on fluorene neurotoxicity, this study was conducted in adult rats to assess the behavioral toxicity of repeated fluorene inhalation exposure. Male rats (n?=?18/group) were exposed nose-only to 1.5 or 150 ppb of fluorene 6 hours/day for 14 consecutive days, whereas the control animals were exposed to non-contaminated air. At the end of the exposure, animals were tested for activity and anxiety in an open-field and in an elevated-plus maze, for short-term memory in a Y-maze, and for spatial learning in an eight-arm maze. The results showed that the locomotor activity and the learning performances of the animals were unaffected by fluorene. In parallel, the fluorene-exposed rats showed a lower level of anxiety than controls in the open-field, but not in the elevated-plus maze, which is probably due to a possible difference in the aversive feature of the two mazes. In the same animals, increasing blood and brain levels of fluorene monohydroxylated metabolites (especially the 2-OH fluorene) were detected at both concentrations (1.5 and 150 ppb), demonstrating the exposure of the animals to the pollutant and showing the ability of this compound to be metabolized and to reach the cerebral compartment. The present study highlights the possibility for a 14-day fluorene exposure to induce some specific anxiety-related behavioral disturbances, and argues in favor of the susceptibility of the adult brain when exposed to volatile fluorene.
Toxicology and Applied Pharmacology, 271 (2), pp. 175-183.
Schellenberger, M.T., Grova, N., Farinelle, S., Willième, S., Schroeder, H., Muller, C.P.
Benzo[a]pyrene (B[a]P) is a small molecular weight carcinogen and the prototype of polycyclic aromatic hydrocarbons (PAHs). While these compounds are primarily known for their carcinogenicity, B[a]P and its metabolites are also neurotoxic for mammalian species. To develop a prophylactic immune strategy against detrimental effects of B[a]P, female Balb/c mice immunized with a B[a]P-diphtheria toxoid (B[a]P-DT) conjugate vaccine were sub-acutely exposed to 2mg/kg B[a]P and behavioral performances were monitored in tests related to learning and memory, anxiety and motor coordination. mRNA expression of the NMDA receptor (NR1, 2A and 2B subunits) involved in the above behavioral functions was measured in 5 brain regions. B[a]P induced NMDA1 expression in three (hippocampus, amygdala and cerebellum) of five brain regions investigated, and modulated NMDA2 in two of the five brain regions (frontal cortex and cerebellum). Each one of these B[a]P-effects was reversed in mice that were immunized against this PAH, with measurable consequences on behavior such as anxiety, short term learning and memory. Thus active immunization against B[a]P with a B[a]P-DT conjugate vaccine had a protective effect and attenuated the pharmacological and neurotoxic effects even of high concentrations of B[a]P.
Toxicology Letters, 211 (2), pp. 105-113.
Crépeaux, G., Bouillaud-Kremarik, P., Sikhayeva, N., Rychen, G., Soulimani, R., Schroeder, H.
Toxicology Letters, 204 (1), pp. 57-63.
Daubie, S., Bisson, J.F., Lalonde, R., Schroeder, H., Rychen, G.
Polybrominated diphenyl ethers (PBDEs) are flame retardants. Because of their high lipophilicity and persistence, PBDEs bioaccumulate in all abiotic and biological matrices. The aim of this study was to investigate the long-term neurobehavioral and physiological effects of exposure to environmental doses of PBDE-99 in adult rats. Rats received a daily administration of PBDE-99 for 90 days by oral gavage at 0.15, 1.5 and 15 µg/kg, doses which are relevant of human exposure. Before and after the 90 days of exposure, behavioral tests including the open-field and the elevated plus-maze tests for locomotor activity and anxiety, and the Morris water maze for spatial learning were conducted. Physiological measures such as body weight, food and water consumption, organs weight, hepatic enzymes levels and PBDE-99 concentration in adipose tissue were also evaluated at the end of exposure. There was no effect on body weight, food and water consumption, organs weight, hepatic enzymes levels despite rising PBDE-99 concentration in adipose tissue with the doses tested. Moreover, there was no effect on locomotor activity and exploration, and spatial learning. Deleterious effects of BDE-99 at high doses have often been highlighted in many studies after an acute dose whereas exposure during 90 days at realistic doses would have no significant effect in adult rats.
Chemical Research in Toxicology, 24 (10), pp. 1653-1667.
Grova, N., Salquèbre, G., Schroeder, H., Appenzeller, B.M.R.
An efficient and selective method for the quantitative determination of polycyclic aromatic hydrocarbons (PAHs) and their monohydroxylated metabolites (OH-PAHs) in rat brain tissue using gas chromatography tandem (triple quadrupole) mass spectrometry (GC–MS/MS) was developed and validated. The list of molecules investigated comprised the 16 PAHs from the US-EPA list and 53 of their OH-PAHs. Brain extract was submitted to enzymatic hydrolysis, followed by liquid–liquid extraction, and then purified by solid-phase extraction. Limits of quantification ranged from 0.6 to 29 pg/mg and from 0.5 to 30 pg/mg for PAHs and OH-PAHs respectively. The analysis of rat brain samples exposed to PAH mixture (0.01–1 mg/kg, 28 days, ip) demonstrated that this method allowed the detection of 16 PAHs and 28 OH-PAHs out of the 69 analytes investigated. Mean concentrations of PAHs in animal brain samples exposed to 1 mg/kg of PAH mixture ranged from 3.0 ± 2 pg/mg for benzo[b]fluoranthene to 146 ± 29 pg/mg for phenanthrene. Concomitantly, mean concentrations of OH-PAHs ranged from 0.49 ± 0.4 to 26.5 ± 23 pg/mg for 2-OH-chrysene and 1-OH-pyrene respectively. This study proves, for the first time, the bioavailability of most of the PAHs and OH-PAHs in mammalian brain tissue and should provide an important new tool for future neurotoxicological studies.
Critical Reviews in Environmental Science and Technology, 41 (22), pp. 2026-2047.
Schroeder, H.
Because the developing brain is highly susceptible to toxic injuries, the effects of early exposure to air pollutants such as polycyclic aromatic hydrocarbons have to be questioned. In addition to direct inhalation, food consumption appears to be the main source of intake for these pollutants in humans. Thus, a risk does exist for newborns and young infants through ingestion of contaminated milk from their mothers or commercial ruminant preparations at a moment of extreme vulnerability for the brain. The author reviews human and animal studies, which provide some evidence of the potent toxicity of polycyclic aromatic hydrocarbons for the developing brain.
Bulletin de Veille Scientifique de l'ANSES, 12, pp. 91-98.
Schroeder, H.
Bulletin de Veille Scientifique de l'ANSES, 13, pp. 85-92.
Schroeder, H.
Bulletin de Veille Scientifique de l'ANSES, 14, pp. 73-78.
Schroeder, H.
Bulletin de Veille Scientifique de l'ANSES, 15, pp. 97-102.
Schroeder, H.
Bulletin de Veille Scientifique de l'AFSSET, 10, pp. 96-101.
Schroeder, H.
Bulletin de Veille Scientifique de l'ANSES, 11, pp. 83-88.
Schroeder, H.
Short hypoxia could attenuate the adverse effects of hyperhomocysteinemia on the developing rat brain by inducing neurogenesis.
Experimental Neurology, 216 (1), pp. 231-238.
Blaise, S.A., Nedelec, E., Alberto, J.M., Schroeder, H., Audonnet, S., Bossenmeyer-Pourie, C., Gueant, J.L., Daval, J.L.
Gestational deficiency in methyl donors such as folate and vitamin B12 impairs homocysteine metabolism and can alter brain development in the progeny. Since short hypoxia has been shown to be neuroprotective in preconditioning studies, we aimed to investigate the effects of brief, non-lesioning neonatal hypoxia (100% N2 for 5 min) on the developing brain of rats born to dams fed either a standard diet or a diet lacking vitamins B12, B2, folate and choline until offspring\'s weaning. While having no influence on brain accumulation of homocysteine and concomitant apoptosis in 21-day-old deficient pups, exposure to hypoxia reduced morphological injury of the hippocampal CA1 layer. It also markedly stimulated the incorporation of bromodeoxyuridine (BrdU) in permissive areas such as the subventricular zone and the hippocampus followed by the migration of new neurons. Scores in a locomotor coordination test (days 19-21) and learning and memory behavior in the eight-arm maze (days 80-84) were found to be significantly improved in rats exposed to hypoxia in addition to the deficient diet. Therefore, by stimulating neurogenesis in rat pups, brief neonatal hypoxia appeared to attenuate the long-term effects of early exposure to a deficiency in nutritional determinants of hyperhomocysteinemia.
Toxicology, 259 (3), pp. 97-106.
Bouayed, J., Desor, F., Rammal, H., Kiemer, A.K., Tybl, E., Schroeder, H., Rychen, G., Soulimani, R.
The harmful effects of exposure to benzo[a]pyrene (B[a]P), which is a neurotoxic pollutant, on mammalian neurodevelopment and/or behaviour as yet remain widely unclear. In the present investigation, we evaluated the impact of the lactational exposure to B[a]P on postnatal development of pups and behaviour of young mice. The neurobiological effects of B[a]P during lactation were also evaluated on pups\' brain. Here, we found that lactational exposure to B[a]P at 2 and 20 mg/kg affects the neuromaturation of pups by significantly decreasing their reflex as highlighted in surface righting reflex and negative geotaxis tests. However, we noted a significant increase in muscular strength of lactationally B[a]P mg/kg-exposed pups, which was probably due to the impact of the exposure to this toxic compound on body weight gain. At the pup stage, lactational exposure to B[a]P also provoked a neurobiological change, which was assessed by determination of neuronal receptor gene expression. Indeed, a significant reduction in gene expression of 5HT1A receptors in pups exposed to B[a]P through lactation was found in comparison to controls. Additionally, attenuation in the expression of MOR1 mRNA was observed, but statistically significant only in animals receiving the higher dose. Neither the expression levels of ADRA1D nor GABAA mRNA were altered. Interestingly, the harmful effects of lactational exposure to B[a]P on behaviour and cognitive function were still found despite a long post-weaning period. Young mice whose mothers were exposed to B[a]P displayed a disinhibition behaviour towards the aversive spaces of the elevated plus maze. Furthermore, a significant increase of spontaneous alternation in the Y-maze was observed, but only in young mice whose mothers were orally exposed to the lower dose of B[a]P. Our results suggest a close link between the neurobiological change highlighted in pups\' brain and the different behavioural disturbances observed during postnatal development period until young adult stage.
Anxiolytic-like effects and safety profile of a tryptic hydrolysate from bovine alpha s1-casein in rats.
Fundamental & Clinical Pharmacology 23 (3), pp. 323-330.
Messaoudi, M., Lalonde, R., Schroeder, H., Desor, D.
The anxiolytic activity and adverse benzodiazepine-like effects of a bovine alpha s1-casein tryptic hydrolysate (CH) were evaluated. The effects of CH orally administered at doses of 5 and 15 mg/kg were compared with those of diazepam (DZ) at 3 mg/kg in the conditioned defensive burying test. Rats treated either with CH at 15 mg/kg or with DZ showed a decrease in anxiety. A drug-related difference was observed in terms of duration, as the anxiolytic-like action of CH was maintained after 7 days with twice-daily administration, whereas that of DZ was not. CH and DZ were then evaluated for their potential effects on memory in a passive avoidance paradigm. CH-treated rats had significantly longer latencies before entering the dark compartment where they were previously delivered a shock, indicating better retention relative to DZ-treated rats. In the final test, CH and DZ were evaluated for place preference, an index of the possible addictive potential of these substances. DZ-treated rats spent more time in the compartment associated with drug exposure than control rats. This effect was not found in CH-treated rats. Thus, CH did not display side effects associated with DZ, despite its affinity for gamma-aminobutyric acid(A) (GABAA) receptors. Specific linking of CH on GABAA receptor function involved in anxiolysis, but not on that implied in memory-impairing effects, may be hypothesized to explain its specific activity. This profile might render it advantageous for nutritional purposes.
Plos One, 4 (12), e8268
Orozco-Barrios, C.E., Battaglia-Hsu, S.F., Arango-Rodriguez, M.L., Ayala-Davila, J., Chery, C., Alberto, J.M., Schroeder, H., Daval, J.L., Martinez-Fong, D., Gueant, J.L.
Variations in illumination, closed wall transparency and/or extramaze space influence both baseline anxiety and response to diazepam in the rat elevated plus-maze.
Behavioural Brain Research, 203 (1), pp. 35-42.
Violle, N., Balandras, F., Le Roux, Y., Desor, D., Schroeder, H.
Numerous methodological-related variables have been demonstrated to influence the baseline anxiety level of rodents exposed to the elevated plus-maze (EPM), raising questions about the sensitivity of this test for the detection of the effects of anxiolytic drugs. Thus, the present study was designed (1) to assess the combined effects of illumination (40-lx red or white light), closed wall type (walls made of translucent or opaque material) and extramaze space size (small or spacious experimental room) on rat behaviour, and (2) to investigate the effects of such parameters on the relevance of the maze for detecting the effects of diazepam orally administrated at the anxiolytic dose of 3 mg/kg. Results indicate that illumination and closed wall type are two main independent parameters that are able to modify the open arm avoidance. Moreover, the closed wall type interacts with the extramaze space size since the reduction of the open arm exploration induced by opaque closed walls is two-fold stronger in the spacious experimental room than in the small one. Finally, the diazepam anxiolytic activity is significantly detected in our laboratory in specific EPM conditions (maze with opaque walls, use of a red light, maze located in a spacious experimental room). In conclusion, the present study demonstrates that an inappropriate baseline anxiety level due to the methodological use of the EPM can dramatically reduce the sensitivity of the maze for the detection of benzodiazepine-related compounds. This study also provides new insights into the perception of the EPM open space in rats.
Sub-acute administration of benzo[a]pyrene (B[a]P) reduces anxiety-related behaviour in adult mice and modulates regional expression of N-methyl-d-aspartate (NMDA) receptors genes in relevant brain regions
Chemosphere, 73 (1 SUPPL.), pp. S295-S302.
Grova, N., Schroeder, H., Farinelle, S., Prodhomme, E., Valley, A., Muller, C.P.
Abnormal glutamatergic transmission caused by modulation of N-methyl-d-aspartate (NMDA) receptors was demonstrated in animal models chronically exposed to various organic micropollutants. Recent developments in neurobiology have implicated these receptors in the regulation of anxiety. In order to investigate anxiety-related effects of benzo[a]pyrene (B[a]P), Balb/c mice were sub-acutely exposed to B[a]P (0.02-200 mg kg-1 day-1, 10 days, i.p.). Their performance was tested in the elevated-plus maze and the hole-board apparatus and the NMDA receptor expression genes (NR1, 2A and 2B subunits) was measured in eight brain regions. Mice treated with 20-200 mg kg-1 B[a]P showed a disproportionate accumulation of B[a]P and its metabolites (in particular, the toxic 7,8-diol-B[a]P) in the blood and even more in the brain. These mice were less anxious than controls in the hole-board test and the elevated-plus maze. This observation was associated with an overexpression of the NMDA NR1 receptor gene and concomitant decreases of the NR2A and NR2B subunits expression in the hippocampus, the hypothalamus and the cerebellum. In the temporal cortex, a significant dose-related decrease of NR2A was observed whereas the other subunits remained unchanged. In conclusion, a sub-acute exposure to B[a]P (20 and 200 mg kg-1) reduced anxiety-related behaviour in adult mice and concomitantly impaired NMDA receptor gene expression in relevant brain regions.
The effects of Garum Armoricum® (GA) on elevated-plus maze and conditioned light extinction tests in rats
Current Topics in Nutraceutical Research, 6 (1), pp. 41-45.
Messaoudi, M., Lalonde, R., Nejdi, A., Bisson, J.-F., Rozan, P., Javelot, H., Schroeder, H.
Garum Armoricum® (GA), a compound rich in polyunsaturated fatty acids, free amino acids, small peptides, vitamins and minerals, was evaluated on two fear-related assays in rats. GA and diazepam (DZP) increased entries into open arms relative to placebo, as well as percentage of open arm entries in the elevated plus-maze test. In a similar fashion, all drugged groups spent more time inside the open arms and less time inside the enclosed arms. After a two-day period of conditioned avoidance learning of an aversive bright light, GA and vehicle groups successfully discriminated the active from the inactive lever. On the initial day of acquisition, GA and piracetam (PIR) groups achieved successful discrimination though the control group did not. These results indicate that GA may have anxiolytic-like effects without causing learning deficiencies. These psychotropic properties of GA may be due to the synergistic action of its active constituents.
Gestational vitamin B deficiency leads to homocysteine-associated brain apoptosis and alters neurobehavioral development in rats
American Journal of Pathology, 170 (2), pp. 667-679.
Blaise, S.A., Nedelec, E., Schroeder, H., Alberto, J.-M., Bossenmeyer-Pourie, C., Gueant, J.-L., Daval, J.-L.
Hyperhomocysteinemia has been identified as a risk factor for neurological disorders. To study the influence of early deficiency in nutritional determinants of hyperhomocysteinemia on the developing rat brain, dams were fed a standard diet or a diet lacking methyl groups during gestation and lactation. Homocysteinemia progressively increased in the offspring of the deficient group and at 21 days reached 13.3 ± 3.7 µmol/L versus 6.8 ± 0.3 µmol/L in controls. Homocysteine accumulated in both neurons and astrocytes of selective brain structures including the hippocampus, the cerebellum, the striatum, and the neurogenic subventricular zone. Most homocysteine-positive cells expressed p53 and displayed fragmented DNA indicative of apoptosis. Righting reflex and negative geotaxis revealed a delay in the onset of integration capacities in the deficient group. Between 19 and 21 days, a poorer success score was recorded in deficient animals in a locomotor coordination test. A switch to normal food after weaning allowed restoration of normal homocysteinemia. Nevertheless, at 80 days of age, the exploratory behavior in the elevated-plus maze and the learning and memory behavior in the eight-arm maze revealed that early vitamin B deprivation is associated with persistent functional disabilities, possibly resulting from the ensuing neurotoxic effects of homocysteine.
Modulation of behavior and NMDA-R1 gene mRNA expression in adult female mice after sub-acute administration of benzo(a)pyrene
NeuroToxicology, 28 (3), pp. 630-636.
Grova, N., Valley, A., Turner, J.D., Morel, A., Muller, C.P., Schroeder, H.
The behavioral performances of adult mice exposed to sub-acute doses of benzo(a)pyrene (B(a)P) were monitored in tests related to learning and memory (Y maze and Morris water maze), locomotor activity (open-field test) and motor coordination (Locotronic apparatus). At low doses (0.02 and 0.2 mg/kg), B(a)P impaired short-term learning and spatial memory performance in the Y maze and in the Morris water maze tests. Surprisingly, in the Y maze, the performances of animals exposed to the highest dose of B(a)P (200 mg/kg) were quite similar to those of control animals. Hyperactivity/hyperarousal observed in both tests at this dose and attributed to an anxiolytic-like effect of B(a)P may have blurred the learning deficit in these mice faced with a new situation. These deficits seem to be unrelated to motor impairments because B(a)P had no effect on locomotor activity and motor coordination. We demonstrated that sub-acute exposure to B(a)P in adult mice also modulates gene expression of NMDA-R1 subunit in brain areas highly involved in cognitive function like the hippocampus, suggesting a relationship between the expression of functional NMDA-R1 mRNA, impairment of short-term and spatial memory and the B(a)P exposure levels.
Ethological comparison of the effects of a bovine alpha-s1-casein tryptic hydrolysate and diazepam on the behaviour of rats in two models of anxiety
Pharmacology Biochemistry and Behavior, 84 (3), pp. 517-523.
Violle, N., Messaoudi, M., Lefranc-Millot, C., Desor, D., Nejdi, A., Demagny, B., Schroeder, H.
A bovine alpha-S1-casein tryptic hydrolysate was previously demonstrated to display an anxiolytic-like activity in the conditioned defensive burying and in the elevated plus-maze models when i.p. injected. The present study assessed the anxiolytic-like effects of this tryptic hydrolysate after an oral administration in rats faced to the same behavioural situations using diazepam as a reference. In a first experiment, the behavioural effects of the hydrolysate in the conditioned defensive burying test were investigated at doses ranging 5-50 mg/kg. The results showed that the minimal dose required to elicit an anxiolytic-like activity is 15 mg/kg. In a second experiment, the alpha-S1-casein tryptic hydrolysate (15 mg/kg, p.o.) was demonstrated to display an anxiolytic-like activity similar to diazepam (3 mg/kg, p.o.) in the conditioned defensive burying test and the elevated plus-maze. However, the ethological analysis of behaviour indicated that this hydrolysate has a different activity compared to diazepam. While diazepam induced a disinhibition state in rats, possibly related to the risk-taking behaviour observed after a benzodiazepine ingestion in humans, the tryptic hydrolysate did not display such a side effect. These results suggest that the mechanism of action of the bovine alpha-s1-casein tryptic hydrolysate may differ from that of diazepam.
Phospholipid transfer protein (PLTP) deficiency reduces brain vitamin E content and increases anxiety in mice
FASEB Journal, 19 (2), pp. 296-297.
Desrumaux, C., Risold, P.-Y., Schroeder, H., Deckert, V., Masson, D., Athias, A., Laplanche, H., Le Guern, N., Blache, D., Jiang, X.-C., Tall, A.R., Desor, D., Lagrost, L.
Vitamin E supplementation constitutes a promising strategy in the prevention of neurodegenerative diseases. Here, we show that a phospholipid transfer protein (PLTP) is widely expressed in the brain where it appears to function as a transfer factor for α-tocopherol, the main isomer of vitamin E. PLTP deficiency results in significant depletion of brain α-tocopherol in both homozygous (–30.1%, P<0.0002) and heterozygous (–18.0%, P<0.05) PLTP knocked-out mice. α-tocopherol depletion in PLTP-deficient homozygotes is associated with the elevation of lipofuscin (+25% and +450% increases in cortex and substantia nigra, respectively), cholesterol oxides (+54.5%, P<0.05), and cellular peroxides (+32.3%, P<0.01) in the brain. Complete PLTP deficiency in homozygotes is accompanied by increased anxiety as shown by fewer entries (8.3% vs. 44.4% in controls, P<0.01) and less time spent (1.7% vs. 41.3% in controls, P<0.05) in the open arms of an elevated plus-maze, in the absence of locomotor deterioration. Thus, the vitamin E transfer activity of PLTP appears to be a key process in preventing oxidative damage in the brain, and PLTP-deficient mice could be a new model of the contribution of oxidative brain injury in the etiology of neurodegenerative diseases.
A 5-month period of epilepsy impairs spatial memory, decreases anxiety, but spares object recognition in the lithium-pilocarpine model in adult rats
Epilepsia, 46 (4), pp. 499-508.
Detour, J., Schroeder, H., Desor, D., Nehlig, A.
Purpose: In temporal lobe epilepsy (TLE), interictal behavioral disorders affect patient\'s quality of life. Therefore we studied long-term behavioral impairments in the lithium-pilocarpine (li-pilo) model of TLE. Methods: Eleven li-pilo adult rats exhibiting spontaneous recurrent seizures (SRSs) during 5 months were compared with 11 li-saline rats. Spatial working memory was tested in a radial arm maze (RAM), anxiety in an elevated plus-maze (EPM), and nonspatial working memory in an object-recognition paradigm. Neuronal loss was assessed on thionine brain sections after behavioral testing. Results: In the RAM, the time to complete each session and the number of errors per session decreased over a 5-day period in li-saline rats but remained constant and significantly higher in li-pilo rats. In the EPM, the number of entries in and time spent on open arms were significantly higher in li-pilo than li-saline rats. In the object-recognition task, the two groups exhibited a comparable novelty preference for the new object. Neuronal loss reached 47-90% in hilus, CA1, amygdala, and piriform and entorhinal cortex. Conclusions: In li-pilo rats having experienced SRS for 5 months, performance in the object-recognition task is spared, which suggests that object discrimination remains relatively intact despite extensive damage. Neuronal loss in regions mediating memory and anxiety, such as hippocampus, entorhinal cortex, and amygdala, may relate to impaired spatial orientation and decreased anxiety.
Effect of cadmium on gonadogenesis and metamorphosis in Pleurodeles waltl (urodele amphibian)
Aquatic Toxicology, 64 (2), pp. 143-153.
Flament, S., Kuntz, S., Chesnel, A., Grillier-Vuissoz, I., Tankozic, C., Penrad-Mobayed, M., Auque, G., Shirali, P., Schroeder, H., Chardard, D.
In the amphibian Pleurodeles waltl, steroid hormones play a key role in sex differentiation. Since cadmium has been reported to block receptors of sex steroid hormones, we analyzed the effects of this heavy metal on Pleurodeles larvae gonadogenesis. At stage 42, larvae die in the presence of 10.9 µM Cd in the rearing tap water, with TL50 of 46.3 h, but the concentration of 5.5 µM is tolerated for more than 60 days. When used at 5.5 µM cadmium accumulation measured by atomic absorption spectrophotometry (AAS) in total homogenates of larvae at stage 54 (after 77 days of exposure to the heavy metal) reached 58.1 µg/g of dry weight. At stage 54, we did not detect inhibitory effects on gonadogenesis in larvae reared in the presence of 5.5 µM Cd since stage 42. When the exposure to 5.5 µM Cd was lengthened after stage 54, metamorphosis was delayed and could not be completed. When larvae were exposed to 10.9 µM Cd from stage 54, metamorphosis did not occur and gonad development was stopped. Our study demonstrates a lack of a direct effect of cadmium on sex determination-differentiation but a strong inhibitory effect on metamorphosis, which impairs further gonadal development.
Histopathological alterations and functional brain deficits after transient hypoxia in the newborn rat pup: A long term follow-up
Neurobiology of Disease, 14 (2), pp. 265-278.
Grojean, S., Schroeder, H., Pourie, G., Charriaut-Marlangue, C., Koziel, V., Desor, D., Vert, P., Daval, J.-L.
To assess temporal brain deficits consecutive to severe birth hypoxia, newborn rats were exposed for 20 min to 100% N2. This treatment induced a long-term growth retardation and a delayed, but only transient, neuronal loss (~25%) in the CA1 hippocampus and parietal cortex, starting from 3 days and peaking at 6 days post-hypoxia. The expression profiles of various apoptosis-regulating proteins (including Bcl-2, Bax, p53 and caspase-3) were well correlated to the alterations of nuclear morphology depicted by 4,6-diamidino-2-phenylindole (DAPI). Whereas they confirmed a gradual histological recovery, specific DNA fragmentation patterns suggested that birth hypoxia may transiently reactivate the developmental programme of neuronal elimination. Although they successfully achieved various behavioral tests such as the righting reflex, negative geotaxis, locomotor coordination, and the eight-arm maze tasks, both developing and adult hypoxic rats were repeatedly slower than controls, suggesting that birth hypoxia is associated to moderate but persistent impairments of functional capacities.
Free radical production and changes in superoxide dismutases associated with hypoxia/reoxygenation-induced apoptosis of embryonic rat forebrain neurons in culture
Free Radical Biology and Medicine, 29 (12), pp. 1291-1301.
Lievre, V., Becuwe, P., Bianchi, A., Koziel, V., Franck, P., Schroeder, H., Nabet, P., Dauca, M., Daval, J.-L.
Following hypoxia/reoxygenation (6h/96h), cultured neurons from the embryonic rat forebrain undergo delayed apoptosis. To evaluate the participation of oxidative stress and defense mechanisms, temporal evolution of intraneuronal free radical generation was monitored by flow cytometry using dihydrorhodamine 123, in parallel with the study of transcriptional, translational, and activity changes of the detoxifying enzymes Cu/Zn-SOD and Mn-SOD. Two distinct peaks of radical generation were depicted, at the time of reoxygenation (+ 27%) and 48 h later (+ 25%), respectively. Radical production was unaffected by caspase inhibitors YVAD-CHO or DEVD-CHO, which prevented neuronal damage, suggesting that caspase activation is not an upstream initiator of radicals in this model. Cell treatment by vitamin E (100 µM) displayed significant neuroprotection, whereas the superoxide generating system xanthine/xanthine oxidase induced apoptosis. Transcript and protein levels of both SODs were reduced 1 h after the onset of hypoxia, but activities were transiently stimulated. Reoxygenation was associated with an increased expression (139%), but a decreased activity (21%) of the inducible Mn-SOD, whereas Cu/Zn-SOD protein and activity were low and progressively increased until 48 h post-hypoxia, when the second rise in radicals occurred. In spite of a temporal regulation of SODs, which parallels radical formation, oxidative stress might account for neurotoxicity induced by hypoxia.
High-performance liquid chromatographic analysis of muscular interstitial arginine and norepinephrine kinetics - A microdialysis study in rats
Journal of Chromatography B: Biomedical Sciences and Applications, 745 (2), pp. 279-286.
Siaghy, E.M., Devaux, Y., Schroeder, H., Sfaksi, N., Ungureanu-Longrois, D., Zannad, F., Villemot, J.P., Nabet, P., Mertes, P.M.
Complex interactions between the L-arginine/nitric oxide synthase (NOS) pathway and the sympathetic nervous system have been reported. Methods capable of measuring L-arginine and norepinephrine (NE) have mainly been reported for plasma. We report the use of the microdialysis technique combined with high-performance liquid chromatography (HPLC) for measurement of both L-arginine and NE within the same tissue microdialysis sample. The microdialysis probe consisted of linear flexible probes (membrane length: 10 mm, outside diameter: 290 µm, molecular weight cut-off 50 kDa). The method used for L-arginine measurement was HPLC with fluorescence detection, giving a within-run and a between-day coefficient of variation of 2.9 and 12.8%, respectively. The detection limit was 0.5 pM/20 µl injected for L-/D- arginine. The method used for NE measurement was HPLC with electrochemical detection. The coefficients of variation were 4% for within-assay precision and 7.5% for between-assay precision. The detection limit for NE was 1 fmol/20 µl injected. The microdialysis technique coupled with HPLC system was validated in vivo to measure muscular interstitial concentrations of both arginine and NE under baseline conditions and after intravenous infusion of 500 mg/kg of L-arginine or D-arginine. In conclusion, the microdialysis technique coupled to HPLC allows the simultaneous measurements of both L- arginine and NE within the same tissue microenvironment and will enable the study of the complex interactions between the L-arginine/NO pathway and sympathetic nervous system within the interstitial space of different organs.
Transient hypoxia may lead to neuronal proliferation in the developing mammalian brain: From apoptosis to cell cycle completion
Neuroscience, 91 (1), pp. 221-231.
Bossenmeyer-Pourie, C., Chihab, R., Schroeder, H., Daval, J.L.
Cerebral hypoxia/ischemia was shown to induce delayed, apoptotic neuronal death occurring through biochemical pathways potentially sharing common events with cell proliferation. This study was designed to test the hypothesis that a sublethal hypoxia may promote mitotic activity in developing central neurons. After six days in vitro, cultured neurons from the forebrain of 14-day-old rat embryos were exposed to hypoxia (95% N2/5% CO2) for 3 h and re-oxygenated for up to 96 h. Controls were kept in normoxia. As a function of time, cell viability was measured by diphenyltetrazolium bromide, and rates of DNA and protein synthesis were monitored using [3H]thymidine and [3H]leucine, respectively. Morphological features of apoptosis, necrosis and mitosis were scored under fluorescence microscopy after nuclear staining with 4,6-diamidino-2-phenylindole, and the expression profile of proliferating cell nuclear antigen, a cofactor for DNA polymerase, was analysed by immunohistochemistry. Data were compared to those obtained after transient hypoxia for 6 h followed by re-oxygenation for 96 h and which was shown to induce apoptosis. Whereas a 6-h insult reduced cell viability, with 23% of the neurons exhibiting apoptosis by the end of re- oxygenation, a 3-h hypoxia led to a cycloheximide-sensitive increase in the final number of living neurons compared to controls (13%, P < 0.01), with no signs of apoptosis, significantly increased thymidine incorporation into acid-precipitable fraction, and persistent over-expression of proliferating cell nuclear antigen. Accordingly, final score of mitotic nuclei was significantly enhanced. In addition, the cell cycle inhibitor olomoucine (50 µM) prevented apoptosis consecutive to a 6-h hypoxia, but impaired the stimulatory effects of a 3-h insult. These findings support the conclusion that some neurons exposed to sublethal hypoxia may dodge apoptotic death by fully achieving the cell cycle.
Hypoxia/reoxygenation induces apoptosis through biphasic induction of protein synthesis in cultured rat brain neurons
Brain Research, 787 (1), pp. 107-116.
Bossenmeyer, C., Chihab, R., Muller, S., Schroeder, H., Daval, J.-L.
To investigate biochemical events accounting for the outcome of central neurons following hypoxia/reoxygenation, cultured neurons from fetal rat forebrain were exposed to hypoxia (95% N2/5% CO2) for 6 h, and then reoxygenated for up to 96 h. Time-dependent changes in macromolecular biosynthesis were analysed by incorporation of [3H]uridine and [3H]leucine and were coupled to cell viability and lactate dehydrogenase leakage. Morphological features of necrosis and apoptosis were scored following nuclear incorporation of the fluorescent dye 4,6-diamidino-2-phenylindole. Hypoxia led to a 36% reduction of cell viability at the end of the reoxygenation period, while 23% of the neurons exhibited apoptosis. A biphasic increase in the rates of protein synthesis was measured 1 h after the onset of hypoxia (77% above controls) and by 48-h postreoxygenation (72%). The presence of cycloheximide during hypoxia inhibited both peaks of synthesis and prevented the development of apoptosis. Protein electrophoresis outlined specific alterations in constitutive proteins, and immunohistochemistry revealed an overexpression of the pro-apoptotic gene products Bax and ICE. Therefore, hypoxia followed by reoxygenation would trigger sequential changes in synthesis of specific proteins, leading to delayed and mainly apoptotic neuronal death.
Long-term effects of early diazepam exposure on social differentiation in adult male rats subjected to the diving-for-food situation
Behavioral Neuroscience, 112 (5), pp. 1209-1217.
Schroeder, H., Toniolo, A.M., Nehlig, A., Desor, D.
The present study was designed to investigate the consequences of a chronic diazepam (DZ) exposure (10 mg/kg/day) during the first 3 weeks of life on social behavior of adult male rats measured in a situation of restricted access to food, the diving-for-food model. The treatment had no long-term effects on the acquisition of social roles related to feeding. However, DZ-exposed rats were less efficient than controls in carrying food from the feeder to the cage during the 1st session but were able to adapt and improve their performances during the 2nd one. In the home cage, DZ-exposed rats were more aggressive toward conspecifics than controls and compensated for their deficit of food by stealing it from the others. These results suggest that an early DZ exposure has long-term consequences on social behavior of rats, possibly reflecting a reduction of the level of emotionality.
Long-term consequences of neonatal exposure to diazepam on cerebral glucose utilization, learning, memory and anxiety
Brain Research, 766 (1-2), pp. 142-152.
Schroeder, H., Humbert, A.-C., Desor, D., Nehlig, A.
The long-term consequences of neonatal exposure to diazepam (DZP) on behavioral abilities and local cerebral glucose utilization (LCGU) in 12 brain regions involved in the control of memory and anxiety were studied in adult rats. Rat pups received a daily subcutaneous injection of 10 mg/kg DZP or of the dissolution vehicle from postnatal day (P) 2 to 21. Learning and memory were tested in P60-P70 rats over 5 consecutive days in a T maze and an eight-arm maze while anxiety and reaction to novelty were tested in a two- compartment box with a two-step staircase on the enriched side. LCGU was measured in the P60 rat by the quantitative autoradiographic [14C]deoxyglucose method. In the T maze, when performed without delay between the two trials, the rate of alternation was significantly lower in DZP- than in vehicle-exposed rats on the first 2 days of testing and similar in both groups on days 3-5. In the procedure with a 30 s intertrial delay, the rate of alternation was similar in DZP- and vehicle-treated rats on all days of testing. In the eight-arm maze, DZP-treated rats were more active, i.e., entered more arms per minute than control animals. The number of arms entered before the first error was lower on day 1 and higher on day 3 in DZP- compared to vehicle-exposed rats. In the two-compartment box, DZP-treated rats crossed more often and spent more time than controls on the lower step of the staircase while control rats made more matings and spent more time than DZP-exposed rats in the wall protected comer of the box. LCGU were decreased by early DZP exposure in six regions which were mammillary body, septum, visual and prefrontal cortices, dorsomedian caudate nucleus and mediodorsal thalamus. In conclusion, postnatal DZP treatment induced at adulthood an increase in activity, a delay in task acquisition but no learning-memory impairment and reduced the level of anxiety allowing active responding to novelty. These quite subtle behavioral changes were accompanied by discrete metabolic decreases in regions mediating anxiety, reflecting a change in the level of anxiety and emotionality.
Early chronic exposure to diazepam, cerebral metabolism and behavior: Long-term consequences. [Exposition chronique precoce au diazepam, metabolisme cerebral et comportement: Consequences a long terme chez le rat adulte]
Encephale, 23 (2), pp. 131-141.
Schroeder, H., Toniolo, A.-M., Desor, D., Nehlig, A.
The long-term consequences of a neonatal exposure to diazepam (DZP) on behavioral abilities and local cerebral metabolic rates for glucose (LCMRglc) in selected brain regions involved in the control of memory and anxiety were studied in adult rats. Rat pups received a daily subcutaneous injection of 10 mg/kg DZP or of the dissolution vehicle from postnatal day (P) 2 to 21. Learning and memory were tested in P60-P70 rats on 5 consecutive days in a T maze and an eight arm maze while anxiety and reaction to novelty were tested in a 2 compartment box with a 2 step staircase on one side. Social behavior was evaluated in a condition of restricted access to food. LCMRglcs were measured at P60 by the quantitative autoradiographic [14C]deoxyglucose method. In the T maze, when performed without delay between the 2 trials, the rate of alternation was significantly lower in DZP than in vehicle-exposed rats on the first 2 days of testing and similar in both groups on days 3-5. In the procedure with a 30 s intertrial delay, the rate of alternation was similar in DZP and vehicle-treated rats on all days of testing. In the eight arm maze, DZP-treated rats were more active, i.e. entering more arms per min than control animals. The number of arms entered before the first error was lower on day 1 and higher on day 3 in DZP compared to vehicle-exposed rats. In the 2 compartment box, DZP-treated rats crossed more often the lower step of the staircase and spent more time than controls on the 2 steps of the staircase while control rats made more rearings than DZP-exposed rats in the well protected corner of the box. LCMRglcs were decreased by early DZP exposure in several cortical regions, mammillary body, septum and dorsomedian caudate nucleus. In conclusion, an early chronic DZP treatment induces an increase in activity, only a delay but no impairment in learning and leads to a decrease in the level of anxiety and emotionality leading to an active response to novelty. These quite subtle behavioral changes are accompanied by discrete metabolic changes and probably reflect the state of hyperactivity/hyperarousal of these animals which could result from a change in the distribution, the sensitivity and/or function of GABA-BZD receptors.
Rapid determination of fecal fat by Fourier transform infrared analysis (FTIR) with partial least-squares regression and an attenuated total reflectance accessory
Clinical Chemistry, 42 (12), pp. 2015-2020.
Franck, P., Sallerin, J.-L., Schroeder, H., Gelot, M.-A., Nabet, P.
Fecal lipid content is usually determined by titrimetric or gravimetric methods, but these methods are time consuming and involve dangerous solvents. We have developed a new method of measuring fecal lipids by Fourier transform infrared spectrometry (FTIR) with an attenuated total reflectance accessory that is fast and requires no solvents. The spectra of stools from 4000 to 750 cm-1 were analyzed, and the lipid concentrations were measured by using a calibration curve prepared by partial least-squares analysis of data from 34 stools. The linearity of the method was tested by mixing low-lipid stools with lipid-overloaded stools to give a range of 0.5-15% lipid. The prediction residual values were -0.49-0.78% for calibrators, and -2.55-2.34% for unknown samples. There was good agreement between the fecal lipids measured by gravimetric (x) and FTIR (y) methods:y = 0.87x + 5.5. The standard error of prediction was 1.07%.
Behavioral and metabolic consequences of neonatal exposure to diazepam in rat pups
Experimental Neurology, 131 (1), pp. 53-63.
Schroeder, H., Humbert, A.-C., Koziel, V., Desor, D., Nehlig, A.
The short-term consequences of a neonatal exposure to diazepam (DZP) on neurobehavioral development and postnatal changes in local cerebral metabolic rates for glucose (LCMRglcs) in selected regions were studied in rats. Rat pups received a daily subcutaneous injection of 10 mg/kg DZP or of the dissolution vehicle from Postnatal Day 2 (P2) to 21 (P21). DZP did not affect the static righting reflex tested at P4 but increased suspension time at P10 and time to complete a 180° pivoting on an inclined plane at P9. In a locomotor coordination test performed at P20, swimming or climbing on a vertical pole was not affected by DZP while the drug impaired the ability of the rat to place its hind-paws on the horizontal platform after climbing. Likewise, DZP induced marked decreases (19-45%) in LCMRglcs in most structures studied at P10, P14, and P21. The results of the present study show that neonatal DZP treatment induces motor deficits that appear to be quite subtle, to concern mainly posture and body balance. They are not apparent in tasks such as swimming or climbing but become obvious in more difficult tasks such as achieving a horizontal quadruped position on a platform after a climbing phase, Decreases in cerebral energy metabolism appear to be mainly located in areas controlling posture and body balance and are partly correlated with the locomotor impairments recorded in the present study.
Effects of early chronic diazepam treatment on incorporation of glucose and b-hydroxybutyrate into cerebral amino acids: Relation to undernutrition
International Journal of Developmental Neuroscience, 12 (5), pp. 471-484.
Schroeder, H., Collignon, A., Uttscheid, L., Pereira deVasconcelos, A., Nehlig, A.
The effects of early chronic diazepam (DZP) exposure on blood glucose and ketone body concentration and glucose and ß-hydroxybutyrate (ßHB) utilization for regional cerebral amino acidbiosynthesis were studied in suckling rats. The animals were treated from postnatal day 2 (P2) to 21 (P21) by a daily subcutaneous injection of 10 mg kg DZP or of the dissolution vehicle and studied at PS, P10, P14 and P21, together with an additional group of food-restricted rats obtained by an increase in litter size. DZP treatment induced a 9-26% decrease in body and brain weight. Under nutrition decreased body weight by 20-24% at all ages whereas brain weight was relatively spared. DZP and N-desmethyldiazepam concentrations decreased with age and were cleared from brain and plasma by 6-8 hrs after the injection. DZP decreased plasma glucose concentrations by 6-12% at P5, P14 and P21, whereas undemutrition did not change plasma glucose concentrations, except for a 7% decrease at P14. DZP treatment had no consequences on circulating concentrations of both ketone bodies while undernutrition increased their concentration by 45-362% at all ages. The conversion of [14C]glucose into cerebral amino acids was reduced by DZP at P5 and P10. The cerebral concentration of neurotransmitter arnino acids was not affected by DZP treatment which only increased the amount of neutral amino acids mainly in the cerebellum at PS and P10. After [U-14C]glucose injection, specific radioactivities of cerebral amino acids were mostly decreased by DZP from PS to P14 and significantly increased at P21. With [3-14C]13HB as a precursor, specific radioactivities of neurotransmitter amino acids were increased by DZP. In conclusion, P5 and P10 rats appear to be most sensitive to DZP effects whereas some tolerance to the drug seems to develop by P21. The lack of effects of DZP on blood ketone body concentrations compared to food restriction as well as the relative sparing of brain weight in undernourished rats confirms that the cerebral metabolic consequences of early DZP exposure on brain energy metabolism are mostly direct effects not mediated by sedation-induced undernutrition.
Early chronic exposure to diazepam, cerebral metabolism and behavior. I. Short-term effects. [Exposition chronique au diazépam, métabolisme cérébral et comportement. I. Effets à court terme]
Circulation et Metabolisme du Cerveau, 11 (4), pp. 343-365.
Schroeder, H., Desor, D., Nehlig, A.
The consequences of a chronic neonatal diazepam (DZP) treatment on the postnatal evolution of various aspects of cerebral energy metabolism and on behavior were studied in suckling rats. Animals were treated from postnatal day 2 to 21 by a daily subcutaneous injection of DZP (Valium injectable, Roche) at the dose of 10 mg/kg. Control animals received the same volume of the dissolution vehicle. Measurement of the incorporation of glucose carbon into cerebral amino acids and local cerebral glucose utilization were assessed at 5, 10, 14 and 21 days while behavioral testing was performed at 4, 9, 10 and 20 days. DZP exposure induced a decrease in body weight during the whole period studied as well as a delay in hair appearance. Circulating concentrations of glucose were reduced whereas those of ketone bodies were not affected by the treatment. Incorporation of glucose into amino acids was reduced at 5 and 10 days in the three brain regions studied and local cerebral glucose utilization was decreased essentially in sensory, motor and cortical areas during the same period of development. DZP treatment did not impair rat performances for the righting reflex, swimming or climbing a vertical rod. Conversely, DZP increased the time necessary to the rats to pivot by 180° on an inclined plane and altered their balance abilities, data that are in accordance with the decreases in functional activity in structures controlling balance and visuo-motricity. Finally, DZP prolonged the suspension time at 10 days, certainly as a result of its muscular relaxation properties.
Short- and long-term effects of neonatal diazepam exposure on local cerebral glucose utilization in the rat
Brain Research, 660 (1), pp. 144-153.
Schroeder, H., Nolte, A., Boyet, S., Koziel, V., Nehlig, A.
The short- and long-term consequences of a neonatal exposure to diazepam (DZP) on the postnatal changes in local cerebral metabolic rates for glucose (LCMRglcs) were studied by the quantitative autoradiographic [14C]2-deoxyglucose method in a total number of 66 brain structures of freely moving rats. Rat pups received a daily subcutaneous injection of 10 mg/kg DZP, of the dissolution vehicle or of saline from postnatal day 2 (P2) to 21 (P21). The animals were studied at 4 ages, P10, P14, P21 and P60; DZP induced a decrease in LCMRglcs which was restricted to 13 areas at P10, mainly sensory and limbic regions. At P14, the treatment had significant metabolic effects on 48 structures belonging to all functional systems. By P21, 23 brain areas were still affected by the treatment, mainly sensory, limbic and motor areas. At P60, i.e. at about 40 days after the end of drug exposure, LCMRglcs still decreased in 14 brain regions which were mainly sensory and limbic structures. The structures most sensitive to both short- and long-term consequences of the anticonvulsant treatment are mammillary body, limbic cortices and sensory regions. The dissolution vehicle increased LCMRglcs in few brain regions at P14 and P60, whereas it decreased metabolic levels in 5 brain regions at P21. The results of the present study show that the brain appears to be particularly vulnerable to the treatment at P14, period of active brain growth, whereas by P21, the drug is more actively metabolized and a tolerance to the treatment may occur. The long-term effects of the treatment are in good accordance with the well-known effects of DZP on anxiety, sedation and memory. The structures most sensitive to early neonatal DZP exposure are the mammillary body, limbic cortices and sensory regions that all contain a high density of benzodiazepine binding sites.
Effects of acute administration of a new trimethylxanthine derivative, S 9977-2, on local cerebral blood flow and glucose utilization in the rat
European Journal of Pharmacology, 220 (2-3), pp. 217-229.
Schroeder, H., Dumont, I., Boyet, S., Mocaer, E., Nehlig, A.
S 9977-2 is a new trimethylxanthine derivative with promnesic properties. Its effects on cerebral glucose utilization and blood flow were studied by means of quantitative autoradiography. S 9977-2 was injected intravenously into adult rats at doses of 0.1, 1.0 and 10 mg/kg. At 0.1 mg/kg, S 9977-2 induced a significant increase in cerebral glucose utilization over control values in two white matter areas and in the vestibular nucleus. At 1.0 mg/kg, glucose utilization was affected in 14 areas out of the 63 studied, mainly limbic regions such as the hippocampus, raphe nuclei and locus coeruleus, as well as some posterior areas. Conversely, after the injection of 10 mg/kg S 9977-2, cerebral glucose utilization was similar to that of control rats. At the three doses tested, S9977-2 did not induce any significant variation in local rates of cerebral blood flow compared to those of controls. Likewise, S 9977-2 did not change the level of coupling between cerebral blood flow and metabolism, except at 10 mg/kg, where a relative hypoperfusion at a constant metabolic level was recorded. These data show that, at 1.0 mg/kg, S 9977-2 increased glucose utilization in hippocampal areas, an effect which may be related to the promnesic properties of this compound at the same dose. Moreover, at low doses, the lack of change in the level of coupling between cerebral blood flow and metabolism is indicative of the rather selective action of this compound, compared to that of caffeine. Thus S 9977-2 should have therapeutic effects, mainly via its promnesic properties, without having many side effects.
Effects of the acute administration of a new trimethylxanthine derivative, S 9977-2, on cerebral blood flow and energy metabolism in the rat. [Effets de l'administration aigue d'un nouveau dérvié des triméthylxanthines, le S 9977-2, sur le débit sanguin et le métabolisme énergétique cérébral chez le rat]
Circulation et Metabolisme du Cerveau, 8 (3), pp. 157-174.
Dumont, I., Schroeder, H., Koziel, V., Mocaer, E., Nehlig, A.
Influence of early chronic phenobarbital treatment on cerebral arteriovenous differences of glucose and ketone bodies in the developing rat
International Journal of Developmental Neuroscience, 9 (5), pp. 453-461.
Schroeder, H., Bomont, L., Nehlig, A.
The influence of an early chronic phenobarbital treatment on cerebral arteriovenous differences of glucose, lactate, pyruvate, ß-hydroxybutyrate and acetoacetate was studied in suckling rats. The animals were treated from day 2 to 21 after birth by a daily injection of 50 mg/kg phenobarbital or by saline and were studied at 10, 14 and 21 days. Phenobarbital treatment induced a decrease in cerebral arteriovenous difference of glucose at P14 and no change at P10 and P21. The barbiturate did not have any influence on cerebral arteriovenous difference of lactate and pyruvate at the three stages studied. Cerebral uptake of ß-hydroxybutyrate was unchanged at P10 and increased by two-fold at P14 and by threefold at P21 by phenobarbital. Cerebral arteriovenous difference of acetoacetate was low and did not change with the pharmacological treatment. At P14 and P21, the calculated amount of oxygen used by the brain for the oxidation of ketone bodies was twice as high in barbiturate- as in saline-treated rats and reached values of 47 and 16% respectively in phenobarbital-exposed animals. In addition, the barbiturate seemed to affect the carrier process of ß-hydroxybutyrate from blood to brain. The results of the present study are in good agreement with previous data from our laboratory showing that an early chronic phenobarbital treatment is able to induce a shift in the cerebral energy metabolism balance in favor of ketone bodies.
Effects of caffeine and doxapram administration on local cerebral glucose utilization in the rat. [Effets de l'administration de caféine et de doxapram sur l'utilisation cérébrale locale de glucose chez le rat]
Circulation et Metabolisme du Cerveau, 6 (2), pp. 160-173.
Schroeder, H., Boyet, S., Nehlig
Effects of caffeine and doxapram perfusion on local cerebral glucose utilization in conscious rats
European Journal of Pharmacology, 167 (2), pp. 245-254.
Schroeder, H., Boyet, S., Nehlig, A.
The quantitative autoradiographic 2-[14C]deoxyglucose method was used to measure the effects of a continuous infusion of the respiratory stimulants, caffeine or doxapram, 18 mg/kg per h, on local cerebral glucose utilization in the adult male rat. Local cerebral glucose utilization was measured in 54 cerebral structures from different systems. Caffeine induced widespread increases in energy metabolism, resulting in a significant increase in glucose utilization in 25 structures out of the 54 studied. These increases were distributed within all systems studied, sensory, extrapyramidal motor, limbic and hypothalamic systems. in addition, caffeine induced a non-significant, 10-15%, increase in local cerebral glucose utilization in central respiratory areas. Doxapram infusion did not change the rates of glucose utilization in any of the structures. The rates of local cerebral glucose utilization were significantly lower after doxapram than after caffeine exposure in five cerebral areas, among which were three central respiratory areas. The results confirm the absence of side-effects of doxapram as compared to caffeine when used as respiratory stimulant, especially in neonates. These results also favor a preferentially central action of caffeine on respiratory areas and a more peripheral action of doxapram on chemoreceptors, at least at therapeutic levels.
Effects of early chronic phenobarbital treatment on the maturation of energy metabolism in the developing rat brain. II. Incorporation of ß-hydroxybutyrate into amino acids
Developmental Brain Research, 36 (2), pp. 231-236.
Pereira De Vasconcelos, A., Schroeder, H., Nehlig, A.
The influence of phenobarbital (PhB) on the utilization of ß-hydroxybutyrate by the cerebral cortex and the cerebellum was studied in rats during postnatal maturation. The animals were treated from day 2 to day 35 after birth either by a daily injection of 50 mg/kg PhB or by saline. The rats were studied at 5 postnatal stages: 7, 10, 14, 21 and 35 days. Plasma ß-hydroxybutyrate and acetoacetate levels reached their peak values between 10 and 14 days after birth. The concentration of both ketone bodies was significantly higher in PhB- than in saline-treated rats between 10 and 35 days after birth. The total incorporation of [3-14C]ß-hydroxybutyrate into amino acids reached a peak value at 14 days after birth and was down to very low values at 35 days. It was higher in PhB- than in saline-treated rats. The specific radioactivity values of glutamate, glutamine, aspartate and GABA were significantly higher in PhB- than in saline-treated especially at 10 days after birth. These results demonstrate that a PhB treatment induces an increase in brain ketone body utilization in neonate rats, which is likely to balance the decrease in brain glucose utilization induced by this pharmacological treatment.
Diazepam: Medical Uses, Pharmacology and Health Effects, Walker H.M. and Torres P.A., Eds., Nova Science Publishers, Hauppauge, NY, États-Unis, pp. 1-38
Schroeder, H., Daval, J.-L., Nehlig, A.
Neurodegenerative Diseases - Processes, Prevention, Protection and Monitoring, R. Chuen-Chung Chang, Ed., InTech Open.
Domange, C., Paris, A., Schroeder, H., Pryimenko, N.
Induction expérimentale d’une différenciation sociale chez l’homme.
Acta Cognitica, ARCo’07. C. Bourjot, N. Grégori, H. Schroeder, A. Berardi, Eds., LORIA, Nancy, France, pp. 33-44.
Desor, D., Toniolo, A.M., Schroeder, H.
La situation de difficulté d'accès à la nourriture est un modèle expérimental qui consiste à contraindre des rats à nager en apnée le long d'un aquarium jusqu'à une mangeoire et à rapporter la nourriture ainsi obtenue dans la cage d'habitation, pour pouvoir la consommer. L'apparition de la contrainte aquatique va provoquer, au sein d'un groupe de 6 rats, l'émergence d'une différenciation sociale entre des animaux Transporteurs qui plongent et ramènent ainsi la nourriture, et des individus Non-Transporteurs qui ne plongent jamais et se nourrissent en la volant aux Transporteurs. Ce phénomène est reproductible, stable dans le temps et correspond à un processus auto-organisé dans lequel seraient impliquées des opérations cognitives d'ordre social. Dans le but d'étudier le rôle ou non de tels facteurs chez l'homme, une modélisation de la situation « rat » a été réalisée chez l'homme. Elle consiste à mettre en situation un groupe de 6 sujets au sein d'une activité ludique ayant pour but l'accumulation de points. Sous l'effet de contraintes de plus en plus fortes relatives à l'obtention des points, une structuration sociale émerge menant à l'apparition de rôles similaires à ceux observés dans le modèle animal sur la base des interactions entre les sujets et de la représentation que chacun se fait de cette situation. Ces observations suggèrent un rôle prépondérant de facteurs relevant de la cognition sociale dans l'élaboration et la stabilisation de cette structure.
Processus cognitifs et différenciation sociale de groupes de rats : intérêt de la modélisation multi-agent.
Actes du 6e Colloque des Jeunes Chercheurs en Sciences Cognitives. C. Bresson, N. Gomond, C. Obernesser, J. Rodrigues, Eds., FRESCO, Bordeaux, France, pp. 108-111.
Cotel, M.C., Thomas, V., Bourjot, C., Desor, D., Chevrier, V., Schroeder, H.
Behaviour modulation and expression of N-methyl D-aspartate receptor genes in adult female mice after a chronic administration of Benzo(a)pyrene.
Conference Proceedings of DIOXIN’2005, 25th International Symposium on halogenated Environmental Organic Pollutants & POPs, 20th International Symposium on Polycyclic Aromatic Compounds, 2005, vol. 67, pp. 2376-2378.
Grova, N., Schroeder, H., Valley, A., Turner, J., Muller, C.
The behavioural differentiation between the Carrier and the Non-Carrier profiles in groups subjected to the diving-for-food situation: a complex social model to study anxiety in rodents.
MEASURING BEHAVIOR 2005, 5th International Conference on Methods and Technics in Behavioural Research. L.P. Noldus, F. Grieco, L.W.S. Loijens, P.H. Zimmerman, Eds., Noldus Information Technology, Wageningen, Pays-Bas, pp. 390-393.
Schroeder, H., Desor, D.
Rôle de l'anxiété dans l'émergence de la différenciation sociale de groupes de rats confrontés à une contrainte environnementale relative à l'obtention de nourriture.
Questions de Psychologie Différentielle, A. Flieller, C. Bocerean, J.L. Kop, E. Thiebaut, A.M. Toniolo, J. Tournois, Eds., Presses Universitaires de Rennes, pp. 339-343.
Schroeder, H., Grasmuck, V., Toniolo, A.M., Desor, D.
Consequences of early chronic antiepileptic treatments in animals.
Chilhood epilepsies and brain development. A. Nehlig, J. Motte, P. Plouin, Eds., John Libbey, London, Royaumes-Unis, pp. 289-303.
Pereira de Vasconcelos, A., Schroeder, H., Nehlig, A.
Séminaire de l'école doctorale SIReNa, 26 mars, Dématérialisé
Morel, C., Christophe, A., Maguin-Gaté, K., Jubreaux, J., Degiorgio, C., Bouillaud-Kremarik, P., Grova, N., Schroeder, H.
Evidence is now growing that early-life environmental pollutant exposure during the critical period of brain development may be an important risk factor, contributing to the emergence of neurobehavioral disorders later in life (Grova et al., 2019). In this context, our team previously highlighted that a daily exposure of rat pups to the α isomer of HBCDD, a brominated flame retardant largely added to polystyrene building materials, during gestation and lactation (66 ng/kg/day) induced disturbances in locomotor maturation, exploratory activity and level of anxiety over the first 6 weeks of postnatal life (Maurice et al., 2015). The present study therefore aims at evaluating the developmental neurotoxicity of an early exposure to this chemical that is considered as a compound of high concern for human health, in comparison with valproic acid (VPA), a common anti-epileptic drug known to induce developmental disorders and contribute to the emergence of autism spectrum disorders. HBCDD-exposed dams were administered daily p.o. from GD0 to PND21 with 100 ng/kg/day of α-HBCDD isomer in oil, whereas the two other groups received the vehicle only. At GD12, VPA-treated rats received a single i.p. injection of VPA at a dose of 600 mg/kg whereas the two other groups were injected with the vehicle only. Pups were tested for their early behavioral development from PND3 to PND21 using a standardized test battery. At PND21, brains were collected and cortex removed for further analysis. The results pointed out the ability of both compounds to induce subtle significant behavioral changes during the neurodevelopment with the reduction in the time spent to grasp a rotating grid in VPA-exposed pups at PND9-11 and the increase in the time to move back in the neogative geotaxis task in the HBCDD-treated rats at PND8-10. No significant modification in the olfactory discriminative test (PN9-PND11) has been observed among groups. Cortical protein expression was analyzed for the neuroinflammation and synaptic plasticity, demonstrating a significant increase in the level of glial fibrillary acidic protein (GFAP) associated with a diminution of synaptophysin in the VPA-treated pups whereas HBCDD-exposed rats showed only an increasing level of expression of GFAP. In conclusion, both results suggest the ability of both compounds to impair slightly the brain and behavior development of rat pups in a different way according to the chemicals. The measurements of the cytochrome oxydase activity in various brain regions, currently under progress, should provide us additional information on the impact of an early exposure to HBCDD or VPA on behavioral impairments later in life.
5th International Systems Biomedicine Symposium - Systems neuroscience: bridging the scales of the brain, 5 novembre, Esch-sur-Alzette, Luxembourg
Roth, S., Lamartinière, Y., Fernandes, S.B., Mériaux, S., Maguin Gaté, K., Guebels, P., Godderis, L., Duca, R.C., Bouillaud-Kremarik, P., Turner, J.D., Schroeder, H., Grova, N.
Short- and long-term behavioral impairments related to anxiety, sexual and social behavior have recently been demonstrated in rats daily exposed during gestation and lactation (GD0 to PND21) to α-hexabromocyclododecane (α-HBCDD, 66 ng/kg/day of body weight), a brominated flame retardant of very high concern. The present study is aimed at examining the effects of such exposure on the potent mechanism leading to the phenotypes observed in the cerebellum of male pups at PND14. This brain region is known for its high sensitivity to environmental disturbances occurring essentially during the early phase of brain development. In the cerebellum, we initially assumed that perinatal exposure to α-HBCDD may i) lead to epigenetic changes in the 6-methyl Adenine (6-mA), which has been identified as genuine epigenetic mark through different techniques (LC-MS/MS, DotBlot and immunochemistry) and ii) induce neuroinflammation which could also exert key influence in neuronal dysfunction. The results revealed that α-HBCDD is able to alter the expression levels of proteins associated with neuroinflammation such as GFAP (+10% compared with controls for males and -18% compared to controls for females) and S100β (+ 19% compared with controls in males, p<0.05) which could later interfere in brain development and functioning. Concomitantly, a decrease in males (-30%) in 6mA has been noticed in this part of the brain, suggesting the ability of this contaminant to induce early reduction in DNA methylation. Corresponding IlluminaR sequencing proved that many differential methylated regions (DMR) can be identified on the different chromosomes at PND14 with a particular attention to be paid to changes on the Y and mitochondrial chromosome. This early decrease in 6mA signal intensity was also observed in the cerebellum at the adult stage (PND270) for both female and male exposed animals compared with controls, with a significant interaction between HBCDD and sex (p<0.01). Detailed gene analysis, currently under evaluation, should enable us to understand how the impact of early life α-HBCDD exposure on gene expression induces chronic neuroinflammation and changes in neurotransmission pathways with the occurrence of behavioural impairments later in life as a consequence.
26th International Symposium on Polycyclic Aromatic Compounts (ISPAC), 08-12 septembre, Örebro, Suède
Morel, C., Schroeder, H., Paoli, J., Charalambous, E., Thiebault, C., Guebels, P., Dosen, A., Turner, J.D., Genay, M., Grova, N.
There is growing evidence that supplementation with probiotics improves intestinal transit,
induces systemic protective immune responses and presents beneficial effect on stress
and anxiety. Concomitantly, exposure to Polycyclic Aromatic Hydrocarbons (PAH),
especially in juvenile, proves to induce cognitive developmental delay and behavioral
impairments related to anxiety.
This study provides a proof of concept on the use of probiotic beneficial effect to
counteract the neurotoxic effects induced by PAH. It was carried out by using six groups
of 12 Swiss female mice each . Three groups were daily fed with a mixture of probiotics
for 8 weeks whereas the others received the vehicule only. After 1 month of probiotic
supplementation, the 3 groups of each conditions were exposed by oral gavage to a
mixture of 16-PAHs (3 times per week, 0, 20 and 200 µg/kg, 4 weeks). Neurobehavioural
status related to exploration, anxiety and immediate learning were studied during the last
week of PAH exposure. Faeces were collected, -before, -after 4 weeks of probiotic
supplementation and -at the end of PAH exposure to assess the microbiota balance and
the probiotic viability along the gastro-intestinal tract. Preliminary data showed that
probiotics enable a faster growth of mice compared to controls (p<0.05) and reduce the
loss of weight observed in PAH-treated groups. Enumeration of probiotic strains at several
time point, pointed out that the probiotics survive along the gastro-intestinal tract, but PAH
seems to affect their viability as well as this of microbiota at 200 µg/kg of bw. Analysis of
microbiota by 16S ribosomal RNA gene sequencing should confirm this result. In the lightdark
apparatus, supplementation with probiotics partially restore the decrease of the level
of activity observed in mice exposed to PAH 200 µg/kg (p<0.05). Behavioral analyses
currently under evaluation should enable us to understand how PAH-induced
neurotoxicity and if probiotics may prevent their detrimental effects.
17th biannual meeting of the International Neurotoxicology Association (INA-17) , 28 septembre - 3 octobre, Düsseldorf, Allemagne
Roth, S., Lamartinière, Y., Fernandes, S.B., Mériaux, S., Maguin Gaté, K., Guebels, P., Godderis, L., Duca, R.C., Bouillaud-Kremarik, P., Turner, J.D., Schroeder, H., Grova, N.
Short- and long-term behavioral impairments related to anxiety, sexual and social behavior have been recently demonstrated in rats daily exposed during gestation and lactation (GD0 to PND21) to α-hexabromocyclododecane (α-HBCDD, 66 ng/kg/day of body weight), a brominated flame retardant of very high concern. The present study aimed at examining the effects of such exposure on potent mechanism leading to the observed phenotypes in the cerebellum of male pups at PND14. This part of the brain is known as a structure of high sensitivity to environmental disturbances occurring during the early phase of brain development and of later maturation compared to other brain regions. In cerebellum, we assume that a perinatal exposure to α-HBCDD may i) lead to epigenetic changes of the 6-methyl Adenine (6-mA) that has been identified as genuine epigenetic mark through different techniques (LC-MS/MS, DotBlot and immunochemistry) and ii) induce neuroinflammation which could also play a key role in neuronal dysfunction. The results showed that α-HBCDD is able to change the expression levels of proteins associated to neuroinflammation such as GFAP (+10% compared to controls in male and -18% compared to control in females) and S100β (+ 19% compared to controls in male, p<0.05) which later on could interfere with brain development and functioning. Concomitantly, a decrease in male (-30%) in 6mA has been noticed in this part of the brain, suggesting the ability of this contaminant to induce an early reduction of DNA methylation. Corresponding IlluminaR sequencing proved that many differential methylated regions (DMR) can be identified on the different chromosomes at PND14 with a particular attention to be put on changes on the Y and mitochondrial chromosome. Results under progress showed that this early decrease in 6mA signal intensity was also stated in the cerebellum at the adult stage (PND270) for both female and male-exposed animals compared to controls with a significant interaction between HBCDD and sex (p<0.01). Detailed gene analysis, currently under evaluation, should enable us to understand how the impact of early life α-HBCDD exposure on gene expression may induce chronic neuroinflammation and changes in neurotransmission pathways with the occurrence of behavioural impairments later in life as a consequence.
Microbes – 15ème Congrès National de la Société Française de Microbiologie, 30 septembre - 2 octobre, Paris, France
Morel, C., Schroeder, H., Paoli, J., Charalambous, E., Thiebault, C., Guebels, P., Dosen, A., Turner, J.D., Genay, M., Grova, N.
Introduction and objectives:
There is growing evidence that supplementation with probiotics improves intestinal transit, induces systemic protective immune responses and presents beneficial effect on stress and anxiety. Concomitantly, exposure to Polycyclic Aromatic Hydrocarbons (PAH), especially in juvenile, proves to induce cognitive developmental delay and behavioral impairments related to anxiety. This study provides a proof of concept on the use of probiotic beneficial effect to counteract the neurotoxic effects induced by PAH.
Material and methods:
We studied six groups of 12 Swiss female mice each. Three groups were daily fed with a mixture of probiotics for 8 weeks whereas the others received the vehicule only. After 1 month of probiotic supplementation, the 3 groups of each conditions were exposed by oral gavage to a mixture of 16-PAHs (3 times per week, 0, 20 and 200 µg/kg, 4 weeks). Neurobehavioural status related to exploration, anxiety and immediate learning were studied during the last week of PAH exposure. Faeces were collected, -before, -after 4 weeks of probiotic supplementation and -at the end of PAH exposure to assess the microbiota balance and the probiotic viability along the gastro-intestinal tract.
Results, discussion, conclusion:
Preliminary data showed that probiotics enable a faster growth of mice compared to controls (p<0.05) and reduce the loss of weight observed in PAH-treated groups. Enumeration of probiotic strains at several time point, pointed out that the probiotics survive along the gastro-intestinal tract, but PAH seems to affect their viability as well as this of microbiota at 200 µg/kg of bw. Analysis of microbiota by 16S ribosomal RNA gene sequencing should confirm this result. In the light-dark apparatus, supplementation with probiotics partially restore the decrease of the level of activity observed in mice exposed to PAH 200 µg/kg (p<0.05). Behavioral analyses currently under evaluation should enable us to understand how PAH-induced neurotoxicity and if probiotics may prevent their detrimental effects.
39th Annual Meeting of the NeuroBehavioral Teratology Society & 15th Biennial Meeting of the International Neurotoxicology Society, 27 juin - 01 juillet, Montréal, Canada
Maurice, N., Olry, J., Cariou, R., Marchand, P., Dervilly-pinel, G., Le Bizec, B., Travel, A., Jondreville, C., Schroeder, H.
39th Annual Meeting of the NeuroBehavioral Teratology Society & 15th Biennial Meeting of the International Neurotoxicology Society, 27 juin - 01 juillet, Montréal, Canada
Peiffer, J., Decret, M.J., Nunge, H., Rychen, G., Cosnier, F., Schroeder, H.
Conférence INRS 2015 sur la recherche en santé au travail, "Le Risque Chimique, Méthodes et Techniques Innovantes", 08-10 avril, Nancy, France
Schroeder, H., Domange, C., Labelle, B., Canlet, C., Feidt, C., Pryimenko, N., Rychen, G., Paris, A.
Conférence INRS 2015 sur la recherche en santé au travail, "Le Risque Chimique, Méthodes et Techniques Innovantes", 08-10 avril, Nancy, France
Schroeder, H., Mouton, S., Duca, R., Audry, E., Salquèbre, G., Olry, J., Hardy, E., Grova, N., Bouillaud-Kremarik, P., Appenzeller, B.
11th Annual Conference of the International Metabolomics Society, "Metabolomics 2015", 29 juin - 02 juillet, San Francisco, États-Unis
Canlet, C., Yanibada, B., Amiel, A., Trembaly-Franco, M., Gautier, R., Cravedi, J.P., Ardzivian, A., Desor, F., Peiffer, J., Schroeder, H., Soulimani, R., Debrauwer, L.
ICOH, 31st International Congress on Occupational Health, 31 mai - 05 juin, Séoul, Corée du Sud
Fourneau, C., Boulanger, G., Stucker, I., Huynh, C.K., Garçon, G., Appenzeller, B., Schroeder, H., Sutter, B., Bourgeois, D.
GEC2014, 1st International Congress “Global Environmental Contamination: A challenge for the well-being of the human brain”, 07-10 septembre, Luxembourg, Luxembourg
Labelle-Alvarez, B., Domange, C., Canlet, C., Pryimenko, N., Rychen, G., Feidt, C., Paris, A., Schroeder, H.
EFSA's 2nd Scientific Conference - Shaping the Future of Food Safety, Together, 14-16 octobre, Milan, Italie
Peiffer, J., Desor, F., Ardzivian, A., Schroeder, H., Soulimani, R.
39th Annual Meeting of the NeuroBehavioral Teratology Society & 15th Biennial Meeting of the International Neurotoxicology Society, 27 juin - 01 juillet, Montréal, Canada
Peiffer, J., Desor, F., Ardzivian, A., Schroeder, H., Soulimani, R.
5th National “Science to Practice” Conference, Current Trends in Health Safety and Health Risk Assessment under the Influence of the Environmental Hazards, 21-23 mai, Perm, Russie
Schroeder, H.
Eurotox 2014, 50th Congress of the European Societies of Toxicology, 07-11 septembre, Edimbourg, Royaume-Uni
Grova, N., Hardy, E., Salquèbre, G., Schroeder, H., Appenzeller, B.
Analytical, Clinical and Forensic Toxicology Meeting, 10-13 juin, Bordeaux, France
Appenzeller, B., Hardy, E., Grova, N., Salquèbre, G., Schroeder, H., Duca, R.
GEC2014, 1st International Congress “Global Environmental Contamination: A challenge for the well-being of the human brain”, 07-10 septembre, Luxembourg, Luxembourg
Mouton, S., Schroeder, H., Audry, E., Duca, R., Olry, J., Salquèbre, G., Hardy, E., Grova, N., Bouillaud-Kremarik, P., Appenzeller, B.
DENAMIC International Workshop “New tools and methods for the screening of chemicals for developmental neurotoxicity”, 10-11 mars, Amsterdam, Pays-Bas
Crepeaux, G., Bouillaud-Kremarik, P., Sikhayeva, N., Rychen, G., Soulimani, R., Schroeder, H.
DENAMIC International Workshop “New tools and methods for the screening of chemicals for developmental neurotoxicity”, 10-11 mars, Amsterdam, Pays-Bas
Crepeaux, G., Olry, J., Henry, T., Rychen, G., Soulimani, R., Schroeder, H.
GEC2014, 1st International Congress “Global Environmental Contamination: A challenge for the well-being of the human brain”, 07-10 septembre, Luxembourg, Luxembourg
Peiffer, J., Grova, N., Hidalgo, S., Salquèbre, G., Rychen, G., Bisson, J.-F., Appenzeller, B., Schroeder, H.
Ecole d'été du Département Alimentation Humaine de l'INRA, "La nutrition périnatale et ses conséquences chez l'adulte", 08-11 juillet, La Baule, France
Schroeder, H.
14th International Neurotoxicology Association Meeting, 9-13 Juin, Egmond aan Zee, Pays-Bas
Crepeaux, G., Olry, J.C., Henry, T., Rychen, G., Soulimani, R., Schroeder, H.
14th International Neurotoxicology Association Meeting, 9-13 Juin, Egmond aan Zee, Pays-Bas
Crepeaux, G., Bouillaud-Kremarik, P., Olry, J.C., Feidt, C., Rychen, G., Soulimani, R., Schroeder, H.
23rd SETAC Europe Annual Meeting, 12-16 Mai, Glasgow, Royaume-Uni
Crepeaux, G., Bouillaud-Kremarik, P., Olry, J.C., Gaillard, J., Feidt, C., Rychen, G., Soulimani, R., Schroeder, H.
14th International Neurotoxicology Association Meeting, 9-13 Juin, Egmond aan Zee, Pays-Bas
Crepeaux, G., Bouillaud-Kremarik, P., Sikhayeva, N., Rychen, G., Soulimani, R., Schroeder, H.
Colloque de l'Association pour la Recherche en Toxicologie "Neurotoxicologie comportementale et Toxicologie Sensorielle", 7 et 8 Juin, Paris, France.
Schroeder, H.
Colloque annuel de la Société Cerveau et Maladies Cérébrovasculaires, 20-21 Janvier, Caen, France
Crépeaux, G., Kinzhebayeva, N., Perrin, J.L., Rychen, G., Soulimani, R., Schroeder, H.
Réunion de l'Association de Recherche en Toxicologie, 20-21 juin 2011, Paris, France
Crepeaux, G., Kinzhebayeva, N., Perrin, J.L., Rychen, G., Soulimani, R., Schroeder, H.
5èmes Journées du Réseau Français de Métabolomique et Fluxomique, 28-30 mai 2011, Paris, France
Domange, C., Schroeder, H., Canlet, C., Paris, A., Pryimenko, N.
5èmes Journées du Réseau Français de Métabolomique et Fluxomique, 28-30 mai 2011, Paris, France
Labelle-Alvarez, B., Canlet, C., Domange, C., Pryimenko, N., Rychen, G., Feidt, C., Paris, A., Schroeder, H.
Colloque annuel de la Société Cerveau et Maladies Cérébrovasculaires, 20-21 Janvier, Caen, France
Peiffer, J., Bouillaud-Kremarik, P., Strazielle, C., Schroeder, H.
Journée Scientifique de l’Institut Fédératif de Recherche EFABA, 20 Septembre, Nancy, France
Peiffer, J., Cosnier, F., Grova, N., Nunge, H., Salquebre, G., Decret, M.J., Cossec, B., Rychen, G., Appenzeller, B., Schroeder, H.
BIT's 1st Annual World Congress of Neurotalk 2010, 25-28 Août, Singapour, République de Singapour.
Schroeder, H., Desor, D.
ICT XII, International Congress of Toxicology, 19-23 Juillet, Barcelone, Espagne. Toxicology Letters, 2010, 196 (suppl 1) : S223-S224.
Peiffer, J., Cosnier, F., Wagner, S., Decret, M.J., Cossec, B., Rychen, G., Schroeder, H.
ICT XII, International Congress of Toxicology, 19-23 Juillet, Barcelone, Espagne. Toxicology Letters, 2010, 196 (suppl 1) : S225.
Schroeder, H., Streit, G., Conde, M., Rychen, G., Feidt, C.
Congrès Annuel de la Société Française de Toxicologie, 25-26 Novembre, Paris, France
Crépeaux, G., Kinzhebayeva, N., Perrin, J.L., Rychen, G., Soulimani, R., Schroeder, H.
Séminaire de l'Ecole Doctorale RP2E, 28 Janvier, Nancy, France
Daubié, S., Bisson, J.F., Hidalgo, S., Demade, V., Schroeder, H., Rychen, G.
Séminaire de l'Ecole Doctorale RP2E, 28 Janvier, Nancy, France
Peiffer, J., Cosnier, F., Wagner, S., Decret, M.J., Cossec, B., Rychen, G., Schroeder, H.
Colloque "Système nerveux et environnement", Club de Neurologie de l’Environnement, 19-21 Juin, Sarreguemines, France
Schroeder, H.
Persistent organic pollutants and food safety: a risk for the developing brain
International Conference “Frontiers in Environmental Health, Late Consequences of Early Life Exposure?”, 28 Octobre, Belvaux, Luxembourg
Schroeder, H.
16th North American Regional ISSX Meeting, 18–22 Octobre, Baltimore, USA. Drug Metabolism Reviews, 2009, 41 (suppl 3) : 14.
Priymenko, N., Domange, C., Canlet, C., Traore, A., Bielicki, G., Keller, C., Violle, N., Peiffer, J., Morel, A., Schroeder, H., Paris, A.
Exploration du comportement de souris ingérant une plante réputée neurotoxique chez le cheval, Hypochœris radicata
Colloque de la Société de Circulation et Métabolisme du Cerveau, 2-3 Avril, Nancy, France
Domange, C., Schroeder, H., Morel, A., Peiffer, J., Violle, N., Paris, A., Priymenko, N.
NEUROBEHAVIOURAL TOXICITY OF A 14-DAY EXPOSURE TO THE AIRBORNE POLYCYCLIC AROMATIC HYDROCARBON FLUORENE IN ADULT WISTAR MALE RATS
International Conference “Frontiers in Environmental Health, Late Consequences of Early Life Exposure?”, 28 Octobre, Belvaux, Luxembourg
Peiffer, J., Cosnier, F., Wagner, S., Decret, M.J., Cossec, B., Rychen, G., Schroeder, H.
Effects of an oral sub-acute administration of Benzo[a]pyrene on cerebral CYP1A1/1B1 expression and anxiety-related behaviour in adult mice
Colloque de la Société de Circulation et Métabolisme du Cerveau, 2-3 Avril, Nancy, France
Cao, L., Grova, N., Muller, C.P., Schroeder, H.
Effets neurocomportementaux et physiologiques du BDE-99 administré à faibles doses pendant 90 jours chez le rat mâle Sprague-Dawley
Colloque de la Société de Circulation et Métabolisme du Cerveau, 2-3 Avril, Nancy, France
Daubié, S., Bisson, J.F., Hidalgo, S., Demade, V., Schroeder, H., Rychen, G.
Etude de la toxicité neurocomportementale du fluorène après une exposition répétée par inhalation chez le rat adulte.
Congrès Annuel de la Société Française de Toxicologie, 19-20 Octobre, Nancy, France
Peiffer, J., Cosnier, F., Wagner, S., Décret, M.J., Cossec, B., Rychen, G., Schroeder, H.
Etude des effets comportementaux du fluorène administré par voie intrapéritonéale ou par voie orale pendant 28 jours chez le rat adulte
Colloque de la Société de Circulation et Métabolisme du Cerveau, 2-3 Avril, Nancy, France
Peiffer, J., Morel, A., Hidalgo, S., Rychen, G., Schroeder, H.
Etude de la distribution régionale de l’activité de la cytochrome oxydase dans le cerveau de souris adultes exposées à une administration subaigue de benzo(a)pyrène
Colloque de la Société de Circulation et Métabolisme du Cerveau, 2-3 Avril, Nancy, France
Peiffer, J., Strazielle, C., Schroeder, H.
Investigation of the brain distribution of the neuronal cytochrome oxidase activity in adult mice submitted to a subacute benzo(a)pyrene administration
Congrès Annuel de la Société Française de Toxicologie, 19-20 Octobre, Nancy, France
Peiffer, J., Strazielle, C., Schroeder, H.
Etude de la toxicité neuro-comportementale d’une administration subchronique par voie orale de lait de vache contaminé par des PCB chez le rat adulte.
Congrès Annuel de la Société Française de Toxicologie, 19-20 Octobre, Nancy, France
Streit, G., Condé, M., Rychen, G., Feidt, C., Schroeder, H.
Investigation of the behavioural toxicity of an oral chronic administration of cow milk contaminated with PCBs in rats
International Conference “Frontiers in Environmental Health, Late Consequences of Early Life Exposure?”, 28 Octobre, Belvaux, Luxembourg
Streit, G., Condé, M., Rychen, G., Feidt, C., Schroeder, H.
Effects of an oral subacute administration of benzo(a)Pyrene on cerebral CYP1A1 expression and anxiety-related behaviour in adult mice.
International Conference “Health aspects of indoor and outdoor pollution”, 12 Novembre, Luxembourg Ville, Luxembourg
Cao, L., Grova, N., Muller, C.P., Schroeder, H.
Effects of an oral subacute administration of benzo(a)Pyrene on cerebral CYP1A1 expression and anxiety-related behaviour in adult mice.
EUROTOX 2008 / 45th Congress of the European Societies of Toxicology, 5-8 Octobre, Rhodes, Grèce. Toxicology Letters, 2008, 180 (suppl) : S40.
Cao, L., Grova, N., Muller, C.P., Schroeder, H.
Investigation of the brain distribution of the neuronal cytochrome oxidase activity in adult mice submitted to a subacute benzo(a)Pyrene administration.
EUROTOX 2008 / 45th Congress of the European Societies of Toxicology, 5-8 Octobre, Rhodes, Grèce. Toxicology Letters, 2008, 180 (suppl) : S40
Peiffer, J., Strazielle, C., Schroeder, H.
Brain and behaviour toxicity of airborn pollutants
International Conference “Health aspects of indoor and outdoor pollution”, 12 Novembre, Luxembourg Ville, Luxembourg
Schroeder H.
Combined effects of illumination, closed wall type and extramaze space size on the anxiety-related behavioural baseline of rats submitted to the elevated plus-maze.
MEASURING BEHAVIOR 2008, 6th International Conference on Methods and Techniques in Behavioral Research, 26-29 Août, Maastricht, Pays-Bas
Violle, N., Balandras, F., Le Roux, Y., Desor, D., Schroeder, H.
Tryptic hydrolysate from bovine milk alpha-s1 casein reduces physiological and behavioural responses to an acute stress exposure in Wistar male rat.
FENS 2008, 6th Forum of European Neuroscience Societies, 12-16 Juillet, Genève, Suisse. European Journal of Neuroscience, 2008, 12 (suppl 11) : 91
Violle, N., Desor, D., Gasnier, H., Schroeder, H.
EUROTOX 2008 / 45th Congress of the European Societies of Toxicology, 5-8 Octobre, Rhodes, Grèce. Toxicology Letters, 2008, 180 (suppl) : S124
Labelle-Alvarez, B., Canlet, C., Rychen, G., Feidt, C., Paris, A., Schroeder, H.
International Conference “Health aspects of indoor and outdoor pollution”, 12 Novembre, Luxembourg Ville, Luxembourg
Peiffer, J., Morel, A., Hidalgo, S., Rychen, G., Schroeder, H.
Effets d'une exposition chronique au benzo(a)pyrène sur le comportement relatif à l'anxiété et la mémoire chez la souris adulte : relation avec l'expression régionale des sous-unités NR1, NR2a et NR2b du récepteur NMDA du glutamate.
Réunion de la Société de Circulation et Métabolisme du Cerveau, 26 Janvier, Paris, France
Schroeder, H., Grova, N., Prodhomme, E., Farinelle, S., Valley, A., Muller, C.P.
Effets d’un hydrolysat trypsique de caséine alpha-s1 bovine sur la réponse physiologique comportementale à un stress aigu chez le rat Wistar
Réunion de la Société de Circulation et Métabolisme du Cerveau, 26 Janvier, Paris, France
Violle, N., Miclo, L., Desor, D., Gaillard, J.L., Schroeder, H.
XIth International Congress of Toxicology, 15-19 Juillet, Montréal, Canada
Labelle-Alvarez, B., Canlet, C., Rychen, G., Feidt, C., Paris, A., Schroeder, H.
10th European Nutrition Conference, 10-13 Juillet, Paris, France. Annals of Nutrition & Metabolism, 51 (suppl) : P812
Labelle-Alvarez, B., Paris, A., Feidt, C., Rychen, G., Schroeder, H.,
2èmes Journées d’Animation Scientifique INRA-PHASE, 22 - 24 Octobre, Tours, France
Labelle-Alvarez, B., Canlet, C., Rychen, G., Feidt, C., Paris, A., Schroeder, H.
Effets d'un hydrolysat trypsique de caséine alpha-s1 bovine sur la réponse physiologique et comportementale au stress chez le rat Wistar
Séminaire de l’Ecole Doctorale RP2E, 11 Janvier, Nancy, France
Violle, N., Miclo, L., Desor, D., Gaillard, J.L., Schroeder, H.
Short- and long-term neurobehavioural toxicity of a chronic exposure to benzo(a)pyrene in rodents: a potential role for NMDA receptors ?
International Conference on Food Contaminants and Neurodevelopmental Disorders, 3-5 Décembre, Valence, Espagne
Schroeder, H., Grova, N., Boussel, J., Valley, A., Rychen, G., Muller, C.P.
A chronic administration of Benzo(a)pyrene (BaP) modulates specific behaviours and expression of N-methyl-D-aspartate (NMDA) receptor genes in mice.
EUROTOX 2006 / 6th CTDC Congress & 43rd Congress of the European Societies of Toxicology, 20-24 Septembre, Cavtat, Croatie. Toxicology Letters, 164 (suppl) : S25-S26
Schroeder, H., Grova, N., Prodhomme, E., Farinelle, S., Valley, A., Muller, C.P.
EUROTOX 2006 / 6th CTDC Congress & 43rd Congress of the European Societies of Toxicology, 20-24 Septembre, Cavtat, Croatie. Toxicology Letters, 164 (suppl) : S80-S81
Boussel, J., Grova, N., Feidt, C., Desor, D., Rychen, G., Schroeder, H.
Combined effects of early vitamin-deficiency and neonatal hypoxia on homocysteine levels and neurobehavioral development in rats.
7e Colloque de la Société des Neurosciences, 18-20 Mai, Lille, France
Blaise S., Nedelec E., Alberto J.M., Schroeder H., Gueant J.L., Daval J.L.
Processus cognitifs et différenciation sociale de groupes de rats : intérêt de la modélisation multi-agent.
6e Colloque des Jeunes Chercheurs en Sciences Cognitives, 2-4 Mai, Bordeaux, France
Cotel M.C., Thomas V., Bourjot C., Desor D., Chevrier V., Schroeder H.
Effets d'un traitement chronique au benzo(a)pyrène sur l'expression des récepteurs NMDA du glutamate et le comportement chez la souris adulte.
2e Congrès de la Société Française de Nutrition, 17-19 Novembre, Marseille, France
Grova, N., Schroeder, H., Valley, A., Rychen, G., Muller, C.P.
Relationship between individual anxiety profiles of Wistar male rats and the acquisition of the social status (Carrier/Non-Carrier) in the diving-for-food paradigm.
7e Colloque de la Société des Neurosciences, 18-20 Mai, Lille, France
Schroeder H., Vakanas G.
Carrier/Non-Carrier differentiation of groups of rats faced to the diving-for-food situation: the acquisition of social roles is related to individual anxiety levels.
MEASURING BEHAVIOR 2005, 5th International Conference on Methods and Techniques in Behavioral Research, 30 Août-2 Septembre, Wageningen, Pays-Bas
Schroeder, H., Desor, D.
Individual traits related to anxiety and social adaptation of male rats in the diving-for-food paradigm.
37th Annual General Meeting of the European Brain & Behavior Society, 24-28 septembre, Dublin, Irelande. Acta Neurobiologica Experientia, 2005, 65 (suppl) : P249
Schroeder, H., Vakanas, G.
ING-911, a trypsic hydrolysate from bovine milk alpha-s1-casein, reduces the behavioural anxiety response of Wistar male rats in the conditioned defensive burying paradigm and the elevated plus maze test.
7e Colloque de la Société des Neurosciences, 18-20 Mai, Lille, France
Violle N., Schroeder H., Messaoudi M., Lefranc-Millot C., Nejdi A., Demagny B., Desor D.
DIOXIN 2005, 25th International Symposium on Halogenated Environmental Organic Pollutants and POPs, 21-26 Août, Toronto, Canada
Grova, N., Schroeder, H., Valley, A., Turner, J., Muller, C.P.
2e Congrès de la Société Française de Nutrition, 17-19 Novembre, Marseille, France
Schroeder, H., Boussel, J., Grova, N., Rychen, G., Desor, D.
Conséquences d'une carence maternelle en groupements méthyle sur le développement cérébral du rat nouveau-né.
Réunion de Printemps de la Société de Circulation et Métabolisme du Cerveau, 17-18 Juin, Dijon, France.
Blaise, S., Alberto, J.M., Nedelec, E., Schroeder, H., Gueant, J.L., Sesiat, T., Kauskot, A., Daval, J.L.
Influence d’une hyperhomocystéinémie précoce sur le développement neurocomportemental du rat.
9ème Journée Nationale Homocystéine, 15-16 Octobre, Grenoble, France. Annales de Biologie Clinique, 2004, 63 (2) : 225.
Blaise, S., Alberto, J.M., Nedelec, E., Schroeder, H., Sesia, T., Gueant, J.L., Daval, J.L.
Phospholipid transfer protein (PLTP) deficiency induces chronic oxidative stress and accelerated aging in mouse brain.
1er Congrés Annuel de la Nouvelle Société Française d?Athérosclérose, 10-12 Juin, Biarritz, France.
Desrumeaux, C., Risold, P.Y., Schroeder, H., Deckert, V., Masson, D., Athias, A., Laplanche, H., Le Guern, N., Jiang, X.C., Tall, A., Desor, D., Lagrost, L.
Conséquences neurocomportementales d'une déficience en PLTP chez la souris : relation avec le stress oxydant.
Réunion de Printemps de la Société de Circulation et Métabolisme du Cerveau, 17-18 Juin, Dijon, France.
Desrumeaux, C., Risold, P.Y., Schroeder, H., Deckert, V., Masson, D., Athias, A., Laplanche, H., Le Guern, N., Jiang, X.C., Tall, A., Desor, D., Lagrost, L.
Etude des propriétés neuroprotectrices de l’acide gamma-hydroxybutyrique (GHB) dans un modèle cellulaire d’hypoxie cérébrale.
Réunion de Printemps de la Société de Circulation et Métabolisme du Cerveau, 17-18 Juin, Dijon, France.
Schroeder, H., Lamarche, F., Franck, P., Emser, W., Daval, J.L.
"Locotronic" : conception d'un appareil destiné à la quantification automatisée de diverses variables de la locomotion du rat.
6e Colloque de la Société des Neurosciences, 13-16 Mai, Rouen, France
Desor, D., Cohen-Salmon, C., Limpas, A., Schroeder, H.
Effects of a sub-chronic diazepam exposure on social behaviour related to food in rat groups exposed to the diving-for-food situation.
35th International Meeting of the European Brain & Behavior Society, 16-20 Septembre, Barcelone, Espagne. Acta Neurobiologica Experientia, 2003, 63 (suppl) : E36.
Schroeder, H., Gelhaye, M., Desor, D.
Influence de la qualité des glucides alimentaires sur les performances d’apprentissage spatial dans le labyrinthe radial de Olton chez le rat.
6e Colloque de la Société des Neurosciences, 13-16 Mai, Rouen, France
Schroeder, H., Ruffin, M.P., Lang, V., Desor, D.
Effects of ING-911, a tryptic hydrolysate from bovine milk alpha-s1-casein, on anxiety of Wistar male rats measured in the conditioned defensive burying paradigm and the elevated plus maze test.
10th International Meeting of the European Behavioural Pharmacology Society, 6-9 Septembre, Anvers, Belgique. Behavioural Pharmacology, 2003, 14 (suppl 1) : S38
Schroeder, H., Violle, N., Messaoudi, M., Lefranc-Millot, C., Nejdi, A., Demagny, B., Desor, D.
Influence du statut social (transporteurs autonomes, transporteurs ravitailleurs, non-transporteurs) sur le comportement du rat mesuré dans 2 modèles d'anxiété : l'enfouissement défensif conditionné et le labyrinthe en croix surélevé.
6e Colloque de la Société des Neurosciences, 13-16 Mai, Rouen, France
Vakanas, G., Desor, D., Schroeder, H.
Université Henri Poincaré - Nancy 1, soutenue le 8 décembre 2011
Schroeder, H.
Etude des effets à court et à long terme sur le développement cérébral d’une exposition survenant au cours de la gestation et/ou de l'allaitement.
