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 and first results of our group indicate that even very transient xenobiotic exposure may result in prolonged induction of some enzymes of the xenobiotic response pathway and...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 and first results of our group indicate that even very transient 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. In addition to this next generation RNA sequencing and downstream pathway analysis also revealed persistent changes in energy, glucose and insulin metabolism. Taken together, the previously observations suggest that transient activation of xenosensors may affect long-term drug metabolism and the risk for metabolic disorders both in the exposed individuals and in their immediate offspring.
The first resulting question to be answered in the project is to characterize the molecular and physiological mechanisms leading to long term induction and transmission to subsequent generations. Currently there are two possible mechanisms explaining long-term induction and multigenerational transmission. Either the observed changes are based on pre-uterine persistent epigenetic changes or they are traceable to direct intrauterine contact mediated by long-term depots of lipophilic xenobiotic substances in adipose tissue. To discriminate between both possibilities we will conduct in-vitro-fertilization experiments. Besides that molecular inquisitions and analysis of gene induction via spermatogenesis, lactation and in different periods of gestation will allow further insight in the cross-generational transmission process. The second objective is to assess the scope of medical drugs inducing heritable long-term effects. Therefore humanized mice will be injected with medically used inducers of the xenobiotica response pathway (e.g. carbamazepine or nevirapine). Afterwards they will be tested for long-term and multigenerational induction. The third sub-project revolves around resulting phenotypic health consequences of the changes in gene expression. To elucidate potential ramifications for the xenobiotic response system or the metabolic status of the individual and their offspring we plan different phenotypic analysis of mice (wild type and diet induced models for metabolic diseases) after long-term induction. Long-range the results of this project might be steps towards an individual risk assessment for adverse drug effects (allowing personalized medication) and an environmentally loading for metabolic diseases.
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