36 Publications depuis 2018
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Probiotics and Antimicrobial Proteins, 15 (2), pp. 387-399.
Hadef, S., Idoui, T., Sifour, M., Genay, M., Dary-Mourot, A.
Twenty-five lactic acid bacterial (LAB) strains have been isolated from traditional goat butter and three types of cheese (dry Klila, frech Klila, and Bouhezza) and evaluated for technological abilities, probiotic properties, and potentials as starter cultures. The twenty-five LAB strains comprised eight strains belonging to Lactobacillus, four strains belonging to Lactococcus, eleven strains belonging to Enterococcus, and two strains belonging to Leuconostoc. A non-hierarchical cluster analysis was performed in order to select the performing strains. After carrying out the preliminary phenotypic characterizations and the probiotic potential, three strains designated as BM10, B15, and C30 belonging to the genus Lactobacillus and Enterococcus with good tolerance to acidity were selected. The strains showed a significant resistance to 0.5% bile salts and 0.4% phenol. Hemolytic activity was not detected; in addition, good hydrophobicity and autoaggregation was obtained. A significant antimicrobial activity was exhibited by all selected strains against Listeria innocua. Genotypic identification by 16S rRNA allowed the identification of B15, BM10, and C30 as Lactobacillus plantarum, Lactobacillus casei, and Enterococcus durans, respectively. The results of the current study suggest that the strains isolated from Algerian fermented dairy products have high potential as probiotic starter cultures in the goat butter and cheese industry.
Pratiques en nutrition, 19 (73), pp. 36-40.
Les consommateurs qui recherchent des produits peu transformés d’origine végétale incluent de nouvelles graines dans leur alimentation. Parfois qualifiées de superaliments, elles sont parées de vertus pour la santé. Si des activités biologiques ont pu être établies dans des modèles, leur transposition à l’échelle de l’individu nécessiterait des études cliniques plus nombreuses. Certaines de ces graines contiennent des substances pouvant exercer un impact sur la biodisponibilité de nutriments ou la sécurité alimentaire.
Consumers by seeking less-processed products of plant origin, are including new seeds in their diet. Sometimes called superfoods, many health effects are attributed to them. While some biological activities was established in models, their transposition to humans would require more clinical studies. Some of these seeds contain substances that can impact the bioavailability of nutrients or food security.
Nutrients, 14 (22), pp. 4777.
Allouche, R., Genay, M., Dary-Mourot, A., Hafeez, Z., Miclo, L.
Streptococcus thermophilus, a food grade bacterium, is extensively used in the manufacture of fermented products such as yogurt and cheeses. It has been shown that S. thermophilus strains exhibited varying anti-inflammatory activities in vitro. Our previous study displayed that this activity could be partially due to peptide(s) generated by trypsin hydrolysis of the surface proteins of S. thermophilus LMD-9. Surface protease PrtS could be the source of these peptides during gastrointestinal digestion. Therefore, peptide hydrolysates were obtained by shaving two phenotypically distinct strains of S. thermophilus (LMD-9 PrtS+ and CNRZ-21N PrtS−) with pepsin, a gastric protease, followed or not by trypsinolysis. The peptide hydrolysates of both strains exhibited anti-inflammatory action through the modulation of pro-inflammatory mediators in LPS-stimulated THP-1 macrophages (COX-2, Pro-IL-1β, IL-1β, and IL-8) and LPS-stimulated HT-29 cells (IL-8). Therefore, peptides released from either PrtS+ or PrtS− strains in the gastrointestinal tract during digestion of a product containing this bacterium may display anti-inflammatory effects and reduce the risk of inflammation-related chronic diseases.
Foods, 11 (8), pp. 1157.
Allouche, R., Hafeez, Z., Papier, F., Dary-Mourot, A., Genay, M., Miclo, L.
Nutrients, 14 (11), pp. 2212.
Benoit, S., Chaumontet, C., Violle, N., Boulier, A., Hafeez, Z., Cakir-Kiefer, C., Tomé, D., Schwarz, J., Miclo, L.
Frontiers in Nutrition, 9, doi:10.3389/fnut.2022.888179.
Gagnaire, V., Lecomte, X., Richoux, R., Genay, M., Jardin, J., Briard-Bion, V., Kerjean, J.-R., Thierry, A.
Pratiques en nutrition, 18 (71), pp. 40-44.
Les polyols sont des édulcorants de masse incorporés dans des produits alimentaires en substitution des sucres. Ils possèdent un pouvoir sucrant et une valeur énergétique inférieurs à ceux du saccharose mais leurs propriétés laxatives limitent leur emploi, bien que celles-ci dépendent largement du polyol considéré. Ce sont des fermentable oligo-, di-, monosaccharides and polyols, dont l’utilisation doit être surveillée chez les personnes sensibles, bien qu’ils aient des effets prébiotiques importants pour le microbiote intestinal.
Polyols are bulk sweeteners used in food products as a substitute for sugars. They have a sweetness and a caloric value lower than those of sucrose, but their laxative effects limit their use although these largely depend on the polyol in question. Being a part of Fermentable Oligo-, Di-, Monosaccharides and Polyols, their use should bear continued scrutiny in sensitive people, knowing that they have major prebiotic effects for the gut microbiota.
Toxics, 10 (4), pp. 180.
Morel, C., Christophe, A., Maguin Gaté, K., Paoli, J., Turner, J.D., Schroeder, H., Grova, N.
Environmental Chemistry Letters, Jan 23, pp. 1-6.
Morel, C., Schroeder, H., Emond, C., Turner, J.D., Lichtfouse, E., Grova, N.
Dying immediately in fames or from poisoning in the long run is the cornelian dilemma induced by the use of brominated fame-retardants. Indeed, these compounds have been intensively used to slow down fres in houses and buildings, thus increasing escape time from about 2 min to 20 min. They were initially thought to be safe, notably because their adhesive properties make them unlikely to reach human tissues. However, recent research has disclosed that brominated fame-retardants are developmental neurotoxicants that trigger neurodevelopmental defcits in young children (Gray and Billock 2017) (Fig. 1). Since infants and young children have been exposed to brominated fame-retardants since the early 1970s, we are now observing the long-term developmental impact of this 50-year-old ticking time bomb. Here we discuss the occurrence of brominated fame-retardants, exposure at home, neurodevelopmental diseases and alternative fame retardants.
Nutrients, 14 (24), pp. 5338.
Pinchaud, K., Hafeez, Z., Auger, S., Chatel, J.-M., Chadi, S., Langella, P., Paoli, J., Dary-Mourot, A., Maguin-Gaté, K., Olivier, J.-L.
Although arachidonic acid (ARA) is the precursor of the majority of eicosanoids, its influence as a food component on health is not well known. Therefore, we investigated its impact on the gut microbiota and gut–brain axis. Groups of male BALB/c mice were fed either a standard diet containing 5% lipids (Std-ARA) or 15%-lipid diets without ARA (HL-ARA) or with 1% ARA (HL + ARA) for 9 weeks. Fatty acid profiles of all three diets were the same. The HL-ARA diet favored the growth of Bifidobacterium pseudolongum contrary to the HL + ARA diet that favored the pro-inflammatory Escherichia–Shigella genus in fecal microbiota. Dietary ARA intake induced 4- and 15-fold colic overexpression of the pro-inflammatory markers IL-1β and CD40, respectively, without affecting those of TNFα and adiponectin. In the brain, dietary ARA intake led to moderate overexpression of GFAP in the hippocampus and cortex. Both the hyperlipidic diets reduced IL-6 and IL-12 in the brain. For the first time, it was shown that dietary ARA altered the gut microbiota, led to low-grade colic inflammation, and induced astrogliosis in the brain. Further work is necessary to determine the involved mechanisms.
BMC Genomics, 23, pp. 210.
Roux, É., Nicolas, A., Valence, F., Siekaniec, G., Chuat, V., Nicolas, J., Le Loir, Y., Guédon, E.
Microorganisms, 9 (11), pp. 2380.
Awussi, A. A., Roux, É., Humeau, C., Hafeez, Z., Maigret, B., Chang, O.K., Lecomte, X., Humbert, G., Miclo, L., Genay, M., Perrin, C., Dary-Mourot, A.
Growth of the lactic acid bacterium Streptococcus thermophilus in milk depends on its capacity to hydrolyze proteins of this medium through its surface proteolytic activity. Thus, strains exhibiting the cell envelope proteinase (CEP) PrtS are able to grow in milk at high cellular density. Due to its LPNTG motif, which is possibly the substrate of the sortase A (SrtA), PrtS is anchored to the cell wall in most S. thermophilus strains. Conversely, a soluble extracellular PrtS activity has been reported in the strain 4F44. It corresponds, in fact, to a certain proportion of PrtS that is not anchored to the cell wall but rather is released in the growth medium. The main difference between PrtS of strain 4F44 (PrtS4F44) and other PrtS concerns the absence of a 32-residue imperfect duplication in the prodomain of the CEP, postulated as being required for the maturation and correct subsequent anchoring of PrtS. In fact, both mature (without the prodomain at the N-terminal extremity) and immature (with the prodomain) forms are found in the soluble PrtS4F44 form along with an intact LPNTG at their C-terminal extremity. Investigations we present in this work show that (i) the imperfect duplication is not implied in PrtS maturation; (ii) the maturase PrtM is irrelevant in PrtS maturation which is probably automaturated; and (iii) SrtA allows for the PrtS anchoring in S. thermophilus but the SrtA of strain 4F44 (SrtA4F44) displays an altered activity.
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.
Food & Function, 12, pp. 1415-1431.
Hafeez, Z., Benoit, S., Cakir-Kiefer, C., Dary, A., Miclo, L.
About one in three people are affected by anxiety disorders during their lifetime. Anxiety episodes can be brief due to a stressful event, but anxiety disorders can last at least 6 months. A wide variety of therapeutic drugs is available for the treatment of anxiety disorders, but due to the associated side effects of these anxiolytics, it is interesting to find alternatives. Some food protein hydrolysates or active peptide fragments present in such hydrolysates provide a natural and promising mean for preventing certain forms of anxiety. To date, only a few numbers of hydrolysates or peptides from food proteins with anxiolytic-like activity have been characterized. Most of these hydrolysates or peptides have displayed potent anxiolytic profiles in animal or clinical studies. The results suggest that these molecules may exert their effects at different levels. This paper reviews data of the structure/activity relationship of anxiolytic peptides, their physiological effects displayed in in vitro and in vivo assays, bioavailability, and safety profiles.
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.
Microbial Genomics, 7 (11), 000654.
Siekaniec, G., Roux, É., Lemane, T., Guédon, É., Nicolas, J.
This study aimed to provide efficient recognition of bacterial strains on personal computers from MinION (Nanopore) long read data. Thanks to the fall in sequencing costs, the identification of bacteria can now proceed by whole genome sequencing. MinION is a fast, but highly error-prone sequencing device and it is a challenge to successfully identify the strain content of unknown simple or complex microbial samples. It is heavily constrained by memory management and fast access to the read and genome fragments. Our strategy involves three steps: indexing of known genomic sequences for a given or several bacterial species; a request process to assign a read to a strain by matching it to the closest reference genomes; and a final step looking for a minimum set of strains that best explains the observed reads. We have applied our method, called ORI, on 77 strains of Streptococcus thermophilus. We worked on several genomic distances and obtained a detailed classification of the strains, together with a criterion that allows merging of what we termed ‘sibling’ strains, only separated by a few mutations. Overall, isolated strains can be safely recognized from MinION data. For mixtures of several non-sibling strains, results depend on strain abundance.
Microorganisms, 9 (6), pp. 1113-1113.
Uriot, O., Kebouchi, M., Lorson-Dalibard, É., Galia, W., Denis, S., Chalançon, S., Hafeez, Z., Roux, É., Genay, M., Blanquet-Diot, S., Dary-Mourot, A.
Despite promising health effects, the probiotic status of Streptococcus thermophilus, a lactic
acid bacterium widely used in dairy industry, requires further documentation of its physiological
status during human gastrointestinal passage. This study aimed to apply recombinant-based in vivo
technology (R-IVET) to identify genes triggered in a S. thermophilus LMD-9 reference strain under
simulated digestive conditions. First, the R-IVET chromosomal cassette and plasmid genomic library
were designed to positively select activated genes. Second, recombinant clones were introduced
into complementary models mimicking the human gut, the Netherlands Organization for Applied
Scientific Research (TNO) gastrointestinal model imitating the human stomach and small intestine,
the Caco-2 TC7 cell line as a model of intestinal epithelium, and anaerobic batch cultures of human
feces as a colon model. All inserts of activated clones displayed a promoter activity that differed
from one digestive condition to another. Our results also showed that S. thermophilus adapted its
metabolism to stressful conditions found in the gastric and colonic competitive environment and
modified its surface proteins during adhesion to Caco-2 TC7 cells. Activated genes were investigated
in a collection of S. thermophilus strains showing various resistance levels to gastrointestinal stresses,
a first stage in the identification of gut resistance markers and a key step in probiotic selection.
Nutrients, 12 (5), 1497.
Benoit, S., Chaumontet, C., Schwarz, J., Cakir-Kiefer, C., Boulier, A., Tomé, D., Miclo, L.
α-Casozepine (α-CZP) is an anxiolytic-like bioactive decapeptide derived from bovine αs1-casein. The N-terminal peptide YLGYL was previously identified after proteolysis of the original peptide in an in vitro digestion model. Its putative anxiolytic-like properties were evaluated in a Swiss mice model using a light/dark box (LDB) after an intraperitoneal injection (0.5 mg/kg). The effect of YLGYL on c-Fos expression in brain regions linked to anxiety regulation was afterwards evaluated via immunofluorescence and compared to those of α-CZP and diazepam, a reference anxiolytic benzodiazepine. YLGYL elicited some anxiolytic-like properties in the LDB, similar to α-CZP and diazepam. The two peptides displayed some strong differences compared with diazepam in terms of c-Fos expression modulation in the prefontal cortex, the amygdala, the nucleus of the tractus solitarius, the periaqueductal grey, and the raphe magnus nucleus, implying a potentially different mode of action. Additionally, YLGYL modulated c-Fos expression in the amygdala and in one of the raphe nuclei, displaying a somewhat similar pattern of activation as α-CZP. Nevertheless, some differences were also spotted between the two peptides, making it possible to formulate the hypothesis that these peptides could act differently on anxiety regulation. Taken together, these results showed that YLGYL could contribute to the in vivo overall action of α-CZP.
Microbiology Resource Announcements, 9 (11), e00129-20
Devaere, M., Boukthir, S., Moullec, S., Roux, É., Lavenier, D., Faili, A., Kayal, S.
The frequency of infections due to Streptococcus pyogenes M/emm89 strains is increasing, presumably due to the emergence of a genetically distinct clone. We sequenced two emm89 strains isolated in Brittany, France, in 2009 and 2010 from invasive and noninvasive infections, respectively. Both strains belong to a newly emerged emm89 clade 3 clone.
International Journal of Molecular Sciences, 21 (14), pp. 5094-5104.
Holuka, C., Merz, M., Fernandes, S.B., Charalambous, E.G., Seal, S.V., Grova, N., Turner, J.D.
A poor socioeconomic environment and social adversity are fundamental determinants of human life span, well-being and health. Previous influenza pandemics showed that socioeconomic factors may determine both disease detection rates and overall outcomes, and preliminary data from the ongoing coronavirus disease (COVID-19) pandemic suggests that this is still true. Over the past years it has become clear that early-life adversity (ELA) plays a critical role biasing the immune system towards a pro-inflammatory and senescent phenotype many years later. Cytotoxic T-lymphocytes (CTL) appear to be particularly sensitive to the early life social environment. As we understand more about the immune response to SARS-CoV-2 it appears that a functional CTL (CD8+) response is required to clear the infection and COVID-19 severity is increased as the CD8+ response becomes somehow diminished or exhausted. This raises the hypothesis that the ELA-induced pro-inflammatory and senescent phenotype may play a role in determining the clinical course of COVID-19, and the convergence of ELA-induced senescence and COVID-19 induced exhaustion represents the worst-case scenario with the least effective T-cell response. If the correct data is collected, it may be possible to separate the early life elements that have made people particularly vulnerable to COVID-19 many years later. This will, naturally, then help us identify those that are most at risk from developing the severest forms of COVID-19. In order to do this, we need to recognize socioeconomic and early-life factors as genuine medically and clinically relevant data that urgently need to be collected. Finally, many biological samples have been collected in the ongoing studies. The mechanisms linking the early life environment with a defined later-life phenotype are starting to be elucidated, and perhaps hold the key to understanding inequalities and differences in the severity of COVID-19.
Food Research International, 131 (x), pp. 108906-108906.
Kebouchi, M., Hafeez, Z., Le Roux, Y., Dary, A., Genay, M.
The mucus, mainly composed of the glycoproteins mucins, is a rheological substance that covers the intestinal epithelium and acts as a protective barrier against a variety of harmful molecules, microbial infection and varying lumen environment conditions. Alterations in the composition or structure of the mucus could lead to various diseases such as inflammatory bowel disease or colorectal cancer. Recent studies revealed that an exogenous intake of probiotic bacteria or other dietary components (such as bioactive peptides and probiotics) derived from food influence mucus layer properties as well as modulate gene expression and secretion of mucins. Therefore, the use of such components for designing new functional ingredients and then foods, could constitute a novel approach to preserve the properties of mucus. After presenting some aspects of the mucus and mucins in the gastrointestinal tract as well as mucus role in the gut health, this review will address role of dietary ingredients in improving mucus/mucin production and provides new suggestions for further investigations of how dietary ingredients/probiotics based functional foods can be developed to maintain or improve the gut health.
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.
Journal of Dairy Science, 102 (1), pp. 113-123.
Hafeez, Z., Cakir-Kiefer, C., Lecomte, X., Miclo, L., Dary, A.
This study addresses the hypothesis that the extracellular cell-associated X-prolyl dipeptidyl-peptidase activity initially described in Streptococcus thermophilus could be attributable to the intracellular X-prolyl dipeptidyl-peptidase PepX. For this purpose, a PepX-negative mutant of S. thermophilus LMD-9 was constructed by interrupting the pepX gene and named LMD-9-delta-pepX. When cultivated, the S. thermophilus LMD-9 wild type strain grew more rapidly than its delta-pepX mutant counterpart. Thus, the growth rate of the LMD-9-delta-pepX strain was reduced by a factor of 1.5 and 1.6 in milk and LM17 medium (M17 medium supplemented with 2% lactose), respectively. The negative effect of the PepX inactivation on the hydrolysis of β-casomorphin-7 was also observed. Indeed, when incubated with this peptide, the LMD-9-delta-pepX mutant cells were unable to hydrolyze it, whereas this peptide was completely degraded by the S. thermophilus LMD-9 wild type cells. This hydrolysis was not due to leakage of intracellular PepX, as no peptide hydrolysis was high-lighted in cell-free filtrate of wild type strain. Therefore, based on these results, it can be presumed that though lacking an export signal, the intracellular PepX might have accessed the β-casomorphin-7 externally, perhaps via its galactose-binding domain-like fold, this domain being known to help enzymes bind to several proteins and substrates. Therefore, the identification of novel distinctive features of the proteolytic system of S. thermophilus will further enhance its credibility as a starter in milk fermentation.
Applied Microbiology and Biotechnology, 103 (6), pp. 2759–2771.
Khaldi, T.E.M., Kebouchi, M., Soligot-Hognon, C., Gomri, M.A., Kharroub, K., Le Roux, Y., Roux, É.
In this study, Streptococcus macedonicus (S. macedonicus) strains were identified from Algerian traditional fermented milks (Lben and Rayeb). Important prerequisites of probiotic interest such as acidity, bile salts tolerance, and adhesion ability to epithelial cells were investigated. A combination of phenotypic (ability to grow on Bile Esculin Azide medium, BEA; on high salt content medium NaCl 6.5%; on alkaline medium pH 9.6) and genotypic approaches (16S rRNA, ITS genes sequencing and MLST technique) allowed to identify four genetically distinct strains of S. macedonicus. These four strains and two references, Streptococcus thermophilus LMD-9 and Lactobacillus rhamnosus GG (LGG), were tested for their capacity to survive at low pH values, and at different concentrations of an equimolar bile salts mixture (BSM). Two different cell lines, Caco-2 TC7 and HT29-MTX, were used for the adhesion study. The results show that S. macedonicus strains selected constitute a distinct genetic entity from the Greek strain S. macedonicus ACA-DC-198. They were able to survive up to pH 3 and could tolerate high concentrations of bile salts (10 mM), unlike LMD-9 and LGG strains. Our strains also display in vitro adhesion similar to the LGG strain on Caco-2 TC7 and higher adhesion than the LMD-9 strain to Caco-2 TC7 and HT29-MTX cell models. This first characterization allows considering S. macedonicus as a potential candidate for possible probiotic effects that need to be investigated.
Environmental Pollution, 255 (1), article 113171.
Le Goff, M., Lagadic-Gossmann, D., Latour, R., Podechard, N., Grova, N., Gauffre, F., Chevance, S., Burel, A., Appenzeller, B.M.R., Ulmann, L., Sergent, O., Le Ferrec, É.
Environmental contaminants, to which humans are widely exposed, cause or worsen several diseases, like cardiovascular diseases and cancers. Among these molecules, polycyclic aromatic hydrocarbons (PAHs) stand out since they are ubiquitous pollutants found in ambient air and diet. Because of their toxic effects, public Health agencies promote development of research studies aiming at increasing the knowledge about PAHs and the discovery of biomarkers of exposure and/or effects.
Extracellular vesicles (EVs), including small extracellular vesicles (S-EVs or exosomes) and large extracellular vesicles (L-EVs or microvesicles), are delivery systems for multimolecular messages related to the nature and status of the originating cells. Because they are produced by all cells and detected within body fluids, EV releases could act as cell responses and thereby serve as biomarkers.
International Journal of Biosciences, 15 (1), pp. 175-184.
Sultana, F., Ahmad, N., Saeed, F., Jalal, F., Hafeez, Z.
Soybean is a good source of dietary proteins associated with numerous nutritional benefits and attenuates metabolic disorders like myocardial infarction (MI). Present study was aimed to explore the role of hydrolysate of extruded soy proteins concentrate (HESPC) intake in mitigation of MI. Isoprenaline induced MI rat groups (3-6) were fed on diet containing 5.07, 10.14, 15.21, 20.30 g proteins from Hydrolysates of extruded soy proteins concentrates (HESPC), respectively. Group 1 (non-induced MI) and group 2 (Isoprenaline induced MI) were fed on casein diet as control. Feed intake, body and heart weight, lactate dehydrogenase (LDH), creatine kinase-MB (CK), troponin, creatinine and urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipid profile, plasma proteins and homocysteine, cardiac and antioxidant enzymes and histopathology analysis were performed. The diet containing HESPC intake significantly changed body and heart weight. Lowest concentrations of LDH, CK-MB and troponin and highest concentration of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were observed in rats group fed on 20.30 g proteins. Blood cells count was significantly decreased on intake of HESPC in all groups. Plasma lipids, proteins, homocysteine, hepatic enzymes showed decreasing trend in rat groups with increasing percentage of HESPC in diet. Histopathological results showed healing of injured heart tissues was significant on HESPC intake. HESPC diet intake can improve biochemical parameters and cardiac tissues health.
Toxicological Sciences, 171 (2), pp. 443-462.
Van Meteren, N., Lagadic-Gossmann, D., Chevanne, M., Gallais, I., Gobart, D., Burel, A., Boucher, S., Bucher, S., Grova, N., Fromenty, B., Appenzeller, B.M.R., Chevance, S., Gauffre, F., Le Ferrec, É., Sergent, O.
Extracellular vesicles (EVs) are membrane-enclosed nanostructures released by cells into the extracellular environment. As major actors of physiological intercellular communication, they have been shown to be pathogenic mediators of several liver diseases. Extracellular vesicles also appear to be potential actors of drug-induced liver injury but nothing is known concerning environmental pollutants. We aimed to study the impact of polycyclic aromatic hydrocarbons (PAHs), major contaminants, on hepatocyte-derived EV production, with a special focus on hepatocyte death. Three PAHs were selected, based on their presence in food and their affinity for the aryl hydrocarbon receptor (AhR): benzo[a]pyrene (BP), dibenzo[a,h]anthracene (DBA), and pyrene (PYR). Treatment of primary rat and WIF-B9 hepatocytes by all 3 PAHs increased the release of EVs, mainly comprised of exosomes, in parallel with modifying exosome protein marker expression and inducing apoptosis. Moreover, PAH treatment of rodents for 3 months also led to increased EV levels in plasma. The EV release involved CYP metabolism and the activation of the transcription factor, the AhR, for BP and DBA and another transcription factor, the constitutive androstane receptor, for PYR. Furthermore, all PAHs increased cholesterol levels in EVs but only BP and DBA were able to reduce the cholesterol content of total cell membranes. All cholesterol changes very likely participated in the increase in EV release and cell death. Finally, we studied changes in cell membrane fluidity caused by BP and DBA due to cholesterol depletion. Our data showed increased cell membrane fluidity, which contributed to hepatocyte EV release and cell death.
Molecular Neurobiology, 56 (2), pp. 892-906.
Willekens, J., Hergalant, S., Pourié, G., Marin, F., Alberto, J.-M., Georges, L., Paoli, J., Nemos, C., Daval, J.-L., Guéant, J.-L., Leininger-Muller, B., Dreumont, N.
Gestational methyl donor (especially B9 and B12 vitamins) deficiency is involved in birth defects and brain development retardation. The underlying molecular mechanisms that are dysregulated still remain poorly understood, in particular in the cerebellum. As evidenced from previous data, females are more affected than males. In this study, we therefore took advantage of a validated rat nutritional model and performed a microarray analysis on female progeny cerebellum, in order to identify which genes and molecular pathways were disrupted in response to methyl donor deficiency. We found that cerebellum development is altered in female pups, with a decrease of the granular cell layer thickness at postnatal day 21. Furthermore, we investigated the involvement of the Wnt signaling pathway, a major molecular pathway involved in neuronal development and later on in synaptic assembly and neurotransmission processes. We found that Wnt canonical pathway was disrupted following early methyl donor deficiency and that neuronal targets were selectively enriched in the downregulated genes. These results could explain the structural brain defects previously observed and highlighted new genes and a new molecular pathway affected by nutritional methyl donor deprivation.
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.
Journal of Nuclear Cardiology, https://doi.org/10.1007/s12350-018-1404-7
Clément, A., Boutley, H., Poussier, S., Pierson, J., Lhuillier, M., Kolodziej, A., Olivier, J.-L., Karcher, G., Marie, P.-Y., Maskali, F.
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.
Oilseeds and fats, Crops and Lipids, 25 (4), pp. D406-D413.
Pinchaud, K., Maguin Gaté, K., Olivier, J.-L.
L’acide arachidonique alimentaire : un acteur à deux faces dans le cerveau et la maladie d’Alzheimer ? L’acide arachidonique est le second acide gras polyinsaturé cérébral et le premier de la série des ω-6. Les apports alimentaires d’acide arachidonique varient entre 50 et 300 mg/jour dans les régimes occidentaux mais pourraient être sous-estimés. Les triglycérides de la partie grasse des viandes fourniraient des quantités similaires aux phospholipides de la partie maigre. La maladie d’Alzheimer est une maladie neurodégénérative associée à l’âge et un problème de santé publique majeur dans le monde. Les oligomères de peptides β amyloïde en sont désormais reconnus comme l’agent principal, bien que la présence de la protéine tau est nécessaire à leur action. Avec d’autres auteurs, nous avons établi que la phospholipase A2 cytosolique, spécifique de l’acide arachidonique, assure les effets neurotoxiques des oligomères de peptide β amyloïde. Nous avons ensuite montré qu’un régime riche en acide arachidonique augmente la sensibilité des souris aux effets de ces oligomères, sans augmentation majeure de ses niveaux cérébraux. Ceci suggère que cet acide gras peut agir sur le cerveau par des effets périphériques comme une sub-inflammation dont le rôle dans la relation intestin-cerveau est discutée dans la littérature. Les apports alimentaires d’acide arachidonique devrait être intégrés dans la prévention de la maladie d’Alzheimer.
Arachidonic acid is the second polyunsaturated fatty acid in brain and the first one belonging to the ω-6 series. Dietary intakes of arachidonic are between 50 and 300 mg/day in western diets but they might be underestimated. Triglycerides from fat would provide similar amounts than phospholipids of lean meat. Alzheimer’s disease is an age-associated degenerative disease and a critical health concern worldwide. Amyloid-β peptide oligomers are presently recognized as the main and earliest agents of Alzheimer’s disease although their neurotoxicity requires the presence of tau protein. We and others established that the arachidonic-specific cytosolic phospholipase A2 is critical for the amyloid-β peptide oligomer neurotoxicity. Then, we showed that an arachidonic acid-rich diet increases the mouse sensitivity to the amyloid-β peptide oligomer deleterious effect without major increase of arachidonic acid levels in brain. This suggests that dietary arachidonic acid can exert its effects in brain through peripheral modifications. Involvement of systemic sub-inflammation and gut-brain communications are discussed based on the recent literature. The various data suggest that dietary arachidonic acid should be taken into account in the design of preventive strategies against Alzheimer’s disease.