Senior research fellow at the Swedish Toxicology
Center Swetox and Karolinska Institutet, Stockholm
Joëlle Rüegg pointed out that there is a lack of understanding mechanisms underlying epigenetic effects of EDCs. She described her findings that the EDC target oestrogen-receptor beta is involved in regulating DNA methylation at specific genomic regions by interacting with thymine DNA glycosylase, an enzyme involved in DNA demethylation (Duong et al, in revision). That oestrogen-receptor beta is directly involved in epigenetic effects of EDCs was shown a study in which BPA exposure during differentiation and development induced DNA methylation changes in a murine hippocampal cell model and in rat hippocampus, respectively (Kitraki et al, 2015). The affected gene, Fkbp5, is an important regulator of the stress axis, and the BPA-exposed rats showed indeed changes in their stress response, thus linking epigenetic changes to a phenotypic outcome (Panagiotidou et al, 2014; Kitraki et al, 2015). The goal is now to study whether it is the interaction between TDG and oestrogen-receptor beta (and other nuclear receptors) that is disturbed by EDCs, and develop simple in vitro assays based on these findings.
Joëlle concluded with a slide about epigenetic transgenerational inheritance and emphasised that also in this case, lack of mechanistic understanding impedes the assessment of its importance. The hypothesis that DNA methylation marks are erased after fertilisation speaks against an epigenetic mechanism for transgenerational inheritance of a phenotype. However, there are exceptions, marks that are either not erased or immediately re-established. How this is achieved and how many exceptions there are is still unknown. Mechanistic understanding would elucidate the role of epigenetic regulation in transgenerational inheritance of phenotypes and hence would clarify our need for test methods for transgenerational effects.