Faculté des Sciences et Technologies - Nancy
Université de Lorraine
03 72 74 57 66 | Chloe.Morel@univ-lorraine.fr
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.
61st Society Of Toxicology annual meeting & ToxExpo, 21-27 mars, San Diego, États-Unis
Morel, C., Emond, C., Duca, R., Debaugnies, F., Borde, P., Paoli, J., Hardy, E., Van Nieuwenhuyse, A., Schroeder, H., Grova, N.
Valproic acid-exposed rat is widely recognized as a validated model to assess Autism Spectrum disorders (ASD-VPA model). However, this model had never been studied for a co-exposure to pollutants like brominated flame retardants (e.g. α-hexabromocyclododecane, α-HBCDD). Both compounds interact on the same xenobiotic metabolism pathway resulting for VPA in the formation of delta-4 VPA, a reactive metabolite known to induce hepatic toxicity. Before assessing the role of α-HBCDD as a factor of susceptibility in the ASD-VPA model, it was essential to characterize VPA pharmacokinetic in α-HBCDD-co-exposure context. The aim of this work was thus to assess the pharmaco- and toxicokinetic involving the VPA/α-HBCDD co-exposure in rat. A sub-acute oral dose of α-HBCDD in oil (100 ng/kg/day) was administered in Wistar female rats for 12 days followed by a single intraperitoneal VPA dose (IP, 500 mg/kg bw) at D12 or a daily oral VPA dose for 3 days (PO, 500 mg/kg bw/day, D10-12). Sequential blood samplings were carried out from 20 min to 18 h after the last VPA administration. The results showed that α-HBCDD did not influence the VPA kinetic independently of the administration mode. The consecutive PO administration of VPA for 3 days did not allow to reach the IP Cmax and was 3.75 times lower than the IP one. In parallel, the toxicokinetic of α-HBCDD was carried out using the same sequential time points. Comparable Cmax values were observed for α-HBCDD only or α-HBCDD-VPA exposed rats by IP whereas a 3-fold increase in α-HBCDD Cmax was highlighted in rats administered with VPA PO. Such discrepancy could suggest an inhibition of CYP3A4 by the delta-4 VPA when VPA is administered for 3 days. A lag time seems therefore to be required to inhibit the metabolic pathway of α-HBCDD. A similar protocol was then carried out to demonstrate the efficiency of VPA/α-HBCDD co-exposure in pregnant rats. This preliminary study enabled to valid the usefulness of the VPA model in a context of α-HBCDD co-exposure, and pointed out, for the first time, the ability of VPA to enhance the internal effective dose of α-HBCDD.
Colloque annuel de la Société Cerveau et Maladies Cérébrovasculaires 2021, 28 mai, Dématérialisé
Morel, C., Maguin Gaté, K., Christophe, A., Jubreaux, J., Paoli, J., Degiorgio, C., Bouillaud-Kremarik, P., Grova, N., Schroeder, H.
Introduction: Evidence is now growing that exposure to environmental pollutants during the critical period of early-life brain development may be a strong risk factor, contributing to the emergence of neurobehavioral disorders later in life. The present study aims at evaluating the developmental neurotoxicity of an early exposure to an environmental chemical of high concern for human health, hexabromocyclododecane (HBCDD), a persistent organobromine flame retardant, in comparison with VPA, a common anti-epileptic drug known to induce developmental disorders including teratogenicity and neurobehavioral disturbances. HBCDD is a brominated flame retardant added to foam materials as a technical mixture of 3 isomers with the α-one to be of most concern for human health. Nowadays, little is known about the neurotoxicity of this isomer. A previous study (Maurice et al., Toxicol. Teratol., 2015) highlighted that a daily exposure of rat pups to α-HBCDD during gestation and lactation (66 ng/kg/day) induced early disturbances in locomotor maturation, exploratory activity and level of anxiety later in life.
Material et Methods: In order to assess neurobehavioral impairments induced by a perinatal exposure to HBCDD or VPA in the F1 generation at different postnatal ages from PND1 to PND122, pregnant Wistar rats were divided into three groups: Control, VPA, and HBCDD. HBCDD-exposed rats were administered daily p.o. during gestation and lactation (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. Anxiety and social behavior were assessed at two time points (juvenile PND 41 and adult age PND 122) by using the elevated-plus-maze and the social recognition test.
Results: The present results point out the ability of both compounds to induce subtle behavioral disturbances that may be quite different between the two chemicals.
Conclusion: The results of the social recognition test associated with the measurements of the cytochrome oxydase activity and epigenetic changes 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.
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.
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.
Mémoire de Master 2ème année mention Sciences du Vivant, parcours Biotechnologies, option Neuro- & Physiologie Appliquée (NPA) (FST, Université de Lorraine)