Abstract
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.
Highlights
Zebrafish appear to represent the most suitable model organism available for studies replicating the effects of endocrine active substances and endocrine disruptors on vertebrates and aquatic wildlife and a model that has great potential for rapid, reliable, and less expensive exploration of the role of epigenetics, aging, senescence, and cancer outcomes in relation to endocrine endpoints, an area that is increasingly important to address in regulatory toxicology, but the current higher level in vivo Test Guidelines (TGs) are unable to address for reasons of high cost, extended time, and the humane concerns related to the extension of such tests
It is possible to state that the evidence far is highly suggestive of a role for epigenomic dysregulation mediating the effects of exposures to endocrine disruptors
These conclusions need to be weighed against the relative weakness of many of the studies performed to date, which have neither been comprehensive nor quantitative, have frequently used in vitro tissue culture systems, or have used mixed cell types from rodent models
Summary
The mechanism by which the group of chemicals referred to as “endocrine disruptors” exert their phenotypic effects remains only partially understood, but there is emerging evidence that dysregulation of the cell’s epigenome is involved. This paper reviews our current understanding of the intersection of these two fields of research and proposes avenues of exploration encompassing epigenetic information that will form the foundation for definitive testing of this relationship and provide a basis for future practical and predictive applications for regulatory safety assessment. How to eventually incorporate the understanding of epigenetic mechanisms into the OECD chemical safety assessment regulatory activities and how this might be done within the ED conceptual framework in vitro screening, priority, and definitive in vivo testing levels, is the major challenge and objective that this paper begins to explore and address. The EDTAAG was established to direct and oversee the development of new or revised Test Guidelines (TGs) for the detection of endocrine active chemicals and endocrine disruptors, as part of the Test Guideline Programme
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