Known and emerging factors modulating estrogenic effects of endocrine-disrupting chemicals

A variety of endocrine-disrupting chemicals (EDCs) have estrogenic effects and are termed xenoestrogens (XEs). The genomic pathway mediated by estrogen receptors (ERs) has been considered the major explanation for the estrogenic effects elicited by XEs. Presently, nongenomic pathways have achieved considerably more attention because the genomic pathways cannot fully elucidate many biological and physiological responses. Genomic and nongenomic pathways act either separately or cooperatively. XEs activate a variety of signaling pathways and downstream kinases, which in turn alter the posttranslational modification and activation of ERs. Classical ERs and their splice variants reside at the membrane and mediate rapid effects cooperatively with G protein-coupled estrogen receptor 1 (GPER), G protein, and many other signaling molecules. GPER seems more effective in mediating the synthetic chemical-induced effects. There are also feedback and feedforward mechanisms between both pathways. Numerous factors may affect both pathways. Recently, some new layers of regulation on the estrogenic effects were identified. In this review, we summarize these multiple regulation layers and discuss the newly identified factors.