Twenty-five years after "Wingspread"- Environmental endocrine disruptors (EDCs) and human health
Citation:
Gray, E. Twenty-five years after "Wingspread"- Environmental endocrine disruptors (EDCs) and human health. Current Opinion in Toxicology. Elsevier BV, AMSTERDAM, Netherlands, 3:40-47, (2017).
Impact/Purpose:
This manuscript is an invited personal "opinion" on the status of EDC screening and testing and the value of research on anti-androgenic Adverse Outcome Pathways in extrapolating molecular from initiating events and key events in an AOP to predict adverse outcomes in laboratory animals and humans.
Description:
The development of life-stage and tissue-specific AOPs for EDCs can reduce the uncertainty in extrapolating of the effects of EDCs from in vitro and in vivo studies in laboratory animals to humans. When the key events (KEs) and molecular initiating event (MIEs) in a pathway are highly conserved among species, as is the case for the androgen (A) and estrogen (E) signaling pathways, there is greater certainty that disruption of the pathway will produce adverse developmental effects among the species. For example, (anti)androgenic chemicals like the AR antagonist flutamide or the androgen agonist trenbolone [1] produce species-typical alterations of the reproductive system in vertebrates [2], because the androgen receptor (AR) pathway is highly conserved from fish to humans. Furthermore, we have found that downstream KEs like fetal testosterone production or inhibition of androgen-dependent tissue growth are better predictors of adverse outcomes of in utero phthalate exposure or AR antagonist exposure, respectively, than are the in vitro assessment of MIEs. There is a much stronger quantitative relationship between the adverse effects of AR antagonists in utero with the effects in an in vivo AR screening assay than with assays of AR binding and in vitro gene expression.
