In vitro and in vivo testing methods of epigenomic endpoints for evaluating endocrine disruptors

Epigenetic modulations underlie critical developmental processes and contribute to determining adult phenotype. Alterations to the phenotype, due to exposure to environmental insults during sensitive periods of development, are mediated through alterations in epigenetic programming in affected tissues. Originally prepared for the Organisation of Economic Cooperation and Development (OECD), this detailed review evaluates the potential role of chemical-induced epigenetic modifications to endocrine signaling pathways during sensitive windows of exposure as a mechanism of endocrine disruption, along with the examination of potential methods for assessing such disruption. Potential targets of disruption along putative adverse outcome pathways associated with the signaling pathways are identified, along with assays that show promise in evaluating the target in a screening and testing program such that in vitro methods are used where possible, and animal experiments only where in vitro methods are not available. Monitoring such epigenetic marks in response to toxicant exposure may in future provide a valuable tool for predicting adverse outcomes, but a more robust basis for Test Guideline recommendations is still needed. Although there is evidence to suggest that epigenomic dysregulation might mediate effects of exposures to endocrine disruptors, it is uncertain as to whether these changes are truly predictive of adverse outcome(s). Adverse effects observed in the OECD transgenerational assays could be used to inform future tests specifically designed to investigate the epigenetic mechanism of action. Follow-up studies should include both an epigenetic as well as a genomic component to differentiate between the contributions of potentially compensatory mechanisms.