Intérêts des cultures in vitro de cellules souches et d’organoïdes dans le cadre d’études toxicologiques

La toxicité de notre environnement et son impact sur la santé préoccupent de plus en plus la population. Certains polluants présents dans l’environnement peuvent affecter l’ensemble de l’environnement et des chaînes trophiques. Dans certains cas, ils peuvent affecter les animaux sauvages, les animaux domestiques, jusqu’à un transfert au sein de l’espèce humaine. Une intoxication correspond à une « introduction ou bio-accumulation d’une substance toxique dans l’organisme ». L’effet de ces substances toxiques est donc important à évaluer pour anticiper ses conséquences sur les organismes. Selon le modèle utilisé, ces évaluations peuvent contenir des biais importants. En effet le métabolisme est différent d’un organisme à l’autre, et donc la capacité à gérer un toxique de l’environnement, à le bio-accumuler ou à l’éliminer est spécifique de l’espèce. La toxicité pour l’animal les assimilant et la disponibilité de ces substances lors de la consommation humaine sont donc très variables. Cette problématique est retrouvée dans un autre contexte toxicologique, celui des drogues médicamenteuses. L’étude toxicologique devrait donc se faire de façon spécifique à l’espèce ciblée, y compris pour l’espèce humaine. En effet un écart important existe entre les résultats obtenus lors des phases pré-cliniques et ceux obtenus lors des essais cliniques. Par ailleurs l’utilisation des modèles animaux fait l’objet d’une réglementation au sein de l’union européenne qui s’attache particulièrement à la limitation de l’utilisation des animaux à des fins scientifiques quand cela est possible. Dans ces contextes se place toute l’importance de méthodes in vitro qui se sont développées au cours des dernières décennies grâce à l’avancée des connaissances fondamentales portant sur les cellules souches, ainsi que des avancées techniques qui y ont été associées. Ces méthodes ont permis la production de cultures en 3 dimensions mimant les structures réelles des organismes, d’où leur nom d’organoïdes. Ces outils deviennent des éléments clés des approches toxicologiques, qu’elles soient liées aux problèmes des expositions à des toxiques ou aux études précliniques humaines et vétérinaires

Aggressive behavior induced by the steroid sulfatase inhibitor COUMATE and by DHEAS in CBA/H mice

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Brain Pathways Mediating the Pro-Aggressive Effect of the Steroid Sulfatase (Sts) Gene

International audienceSTS is the single enzyme that converts all steroid sulfates into their free steroid forms. Initiation of attack behavior against conspecific male mice appeared to be linked to Sts. Here we have confirmed the role of Sts through an association study with attack behavior. Previous studies indicated a positive correlation between the initiation of attack behavior and liver STS concentration levels in male mice, but this finding was not compatible with established knowledge of STS mechanisms. High STS concentrations induce low concentrations of sulfated steroids. Sulfated and un-sulfated steroids are GABA(A) receptor agonists and NMDA receptor positive allosteric modulators. This synaptic pattern of functioning can generate attack behavior and we have confirmed here that an injection of the sulfated steroid dehydroepiandrosterone sulfate (DHEA-S) increases attack behavior. To solve the paradox, we measured the transcription activity of the genes underlying the pathways involved in the hydrolysis of sulfated steroids and leading to the formation of un-conjugated steroids in the mouse brain. We observed that the genes monitoring the steroid biosynthesis pathways exhibited a transcription pattern resulting in an increased sulfotransferase activity in the attacking males that could counterbalance the de-sulfating activity of Sts in the attacking mice

When pharmaceutical drugs become environmental pollutants: Potential neural effects and underlying mechanisms

International audiencePharmaceutical drugs have become consumer products, with a daily use for some of them. The volume of production and consumption of drugs is such that they have become environmental pollutants. Their transfer to wastewater through urine, feces or rinsing in case of skin use, associated with partial elimination by wastewater treatment plants generalize pollution in the hydrosphere, including drinking water, sediments, soils, the food chain and plants. Here, we review the potential effects of environmental exposure to three classes of pharmaceutical drugs, i.e. antibiotics, antidepressants and non-steroidal anti-inflammatory drugs, on neurodevelopment. Experimental studies analyzing their underlying modes of action including those related to endocrine disruption, and molecular mechanisms including epigenetic modifications are presented. In addition, the contribution of brain imaging to the assessment of adverse effects of these three classes of pharmaceuticals is approached

Votre cerveau est-il grignoté par les neuromythes ?

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3Rs-based optimization of mice behavioral testing: The habituation/dishabituation olfactory test

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Perinatal exposure to glufosinate ammonium herbicide impairs neurogenesis and neuroblast migration through cytoskeleton destabilization

Neurogenesis, a process of generating functional neurons from neural precursors, occurs throughout life in restricted brain regions such as the subventricular zone (SVZ). During this process, newly generated neurons migrate along the rostral migratory stream to the olfactory bulb to replace granule cells and periglomerular neurons. This neuronal migration is pivotal not only for neuronal plasticity but also for adapted olfactory based behaviors. Perturbation of this highly controlled system by exogenous chemicals has been associated with neurodevelopmental disorders. We reported recently that perinatal exposure to low dose herbicide glufosinate ammonium (GLA), leads to long lasting behavioral defects reminiscent of Autism Spectrum Disorder-like phenotype in the offspring (Laugeray, Herzine et al. 2014) . Herein, we demonstrate that perinatal exposure to low dose GLA induces alterations in neuroblast proliferation within the SVZ and abnormal migration from the SVZ to the olfactory bulbs. These disturbances are not only concomitant to changes in cell morphology, proliferation and apoptosis, but are also associated with transcriptomic changes. Therefore, we demonstrate for the first time that perinatal exposure to low dose GLA alters SVZ neurogenesis. Jointly with our previous work, the present results provide new evidence on the link between molecular and cellular consequences of early life exposure to the herbicide GLA and the onset of ASD-like phenotype later in life

In utero and lactational exposure to low-doses of the pyrethroid insecticide cypermethrin leads to neurodevelopmental defects in male mice-An ethological and transcriptomic study.

Accumulating evidence suggests that developmental exposure to environmental chemicals may modify the course of brain development, ultimately leading to neuropsychiatric / neurodegenerative disorders later in life. In the present study, we assessed the impact of one of the most frequently used pesticides in both residential and agricultural applications - the synthetic pyrethroid cypermethrin (CYP) - on developmental neurotoxicity (DNT). Female mice were perinatally exposed to low doses of CYP (5 and 20 mg/kg body weight) from gestation to postnatal day 15. Behavioral analyses were performed during the offspring's early life and during adulthood. Postnatal analyses revealed that perinatal exposure to CYP disturbed motor development without modifying sensory and communicative skills. We found that later in life, CYP-exposed offspring expressed maladaptive behaviors in response to highly challenging tasks and abnormal sociability. Transcriptomic analyses performed in the offspring's brain at the end of the exposure, highlighted mitochondrial dysfunction as a relevant pathomechanism underlying CYP-induced DNT. Interestingly, several genes involved in proteostasis maintenance were also shown to be dysregulated suggesting that alterations in biogenesis, folding, trafficking and degradation of proteins may significantly contribute to CYP-related DNT. From a regulatory perspective, this study highlights that behavioral and transcriptomic analyses are complementary tools providing useful direction for better DNT characterization, and as such, should be used together more systematically

Attack behaviors in mice: From factorial structure to quantitative trait loci mapping

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Autisme, génétique et anomalies de la fonction synaptique

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