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 the endobiotic metabolism. However results of our group indicate that even a single xenobiotic exposure may result in prolonged induction of some enzymes of the xenobiotic response pathway and furthermore even a...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 the endobiotic metabolism. However results of our group indicate that even a single xenobiotic exposure may result in prolonged induction of some enzymes of the xenobiotic response pathway and furthermore even a multigenerational transmission of the gene expression changes. Thus, treatment of female mice with an agonist of the drug sensor and transcriptional activator CAR altered in the livers of F1 offspring the expression of genes implicated in the metabolism of xeno- and endobiotics.
The purpose of this project is firstly, to determine if clinically used CAR activators and pollutants are capable of hepatic induction transmission. To this end, female mice will be treated with different CAR activators prior to mating and induction of hepatic CAR-target genes will be assessed.
Secondly, we want to investigate if an exposition in the F0 generation results in clinically relevant phenotypes in the F1 generation. We will determine the drug response, the bone structure and the metabolic status which were previously associated with chronic CAR activation.
Thirdly, the molecular and physiological mechanisms leading to long-term induction and transmission to subsequent generations will be characterized. Currently there are two possible mechanisms explaining long-term induction and multigenerational transmission. Either the observed changes are based on persistent epigenetic changes in the oocyte, or they are traceable to direct intrauterine contact mediated by long-term depots of lipophilic xenobiotic substances in adipose tissue.
The project may uncover an entirely new class of drug side-effects and trigger epidemiological studies of multigenerational drug effects in humans. As the receptor mediating the induction transmission and its target genes are known, this project may also result in an attractive model to study the elusive mechanisms of epigenetic inheritance in general.
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