Kurzfassung

To withstand the exposure to environmental or human-made chemicals including drugs, animals transiently induce the transcription of appropriate metabolizing enzymes and outward transporters. The “on-demand” nature of this detoxifying response may reduce disturbances of endobiotic metabolism. However, a recent report suggests that even very transient xenobiotic exposure may result in life-long induction mediated by epigenetic memory. The first objective of this application is to assess the...To withstand the exposure to environmental or human-made chemicals including drugs, animals transiently induce the transcription of appropriate metabolizing enzymes and outward transporters. The “on-demand” nature of this detoxifying response may reduce disturbances of endobiotic metabolism. However, a recent report suggests that even very transient xenobiotic exposure may result in life-long induction mediated by epigenetic memory. The first objective of this application is to assess the scope of long-term epigenetic memory among the transcriptional targets of the most important human xenosensors, PXR and CAR. The second, objective is to find out if the expression status of PXR and CAR targets is transmitted to the offspring. These questions will be answered in adult mice treated shortly after birth with PXR and CAR activators, and in the offspring of these mice. The global hepatic induction status will be determined by next-generation mRNA sequencing and correlated to epigenetic marks such as histone modifications. These experiments will provide a basis for further grant applications addressing 1) the possibility that long-term epigenetic memory contribute to the inter-individual variability in drug metabolizing capacity, 2) that this memory may contribute to metabolic disorders previously associated with chronic exposure to PXR and CAR activators such as osteopenia and diabetes, 3) the evolutionary significance of long-term epigenetic memory among targets of xenobiotic receptors and 4) mechanisms of long-term epigenetic memory, including the elusive determinants of its transmission via the germline.
The enclosed proposal is very timely and original. It fully integrates into the emerging epigenetic focus of the University, enhanced by the recent establishment of the Institute of Molecular Biology. Granting this proposal should allow for retaining in science a promising female researcher and dedicated teacher. Internal funding is necessary due to the exploratory, hypothesis-generating rather than hypothesis-driven, character of this proposal.
 
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