In a review published on January 31, 2017 in the peer-reviewed journal The Journal of Steroid Biochemistry and Molecular Biology, Angel Nadal and colleagues from Universidad Miguel Hernandez de Elche, Alicante, Spain, discuss the molecular mechanisms of low-dose actions of estrogenic endocrine disrupting chemicals (EDCs), with a particular focus on extranuclear signaling pathways.

Estrogenic EDCs like bisphenol A (BPA, CAS 80-05-7) have long been regarded as weak estrogens acting on estrogen receptors (ERs) to initiate their classic actions as transcription factors in the nucleus. However, mounting evidence suggests that both ER alpha (ERα) and ER beta (ERβ) can also act outside the nucleus, and these actions may or may not involve gene transcription. In addition, a new ER form, a membrane ER, also called G-protein-coupled ER (GPER), has been discovered.

Both BPA and its substitute bisphenol S (BPS, CAS 80-09-1) can act via extranuclear ERα, ERβ, and GPER at nanomolar concentrations, thus within these pathways exhibiting a potency similar to that of the natural hormone, 17β-estradiol. The authors argue that the extranuclear signaling helps explain the estrogenic effects of low doses of EDCs, and the well-known non-monotonic dose-response relationships. They suggest that the estrogenicity of exogenous chemicals should be defined “based on the ability of these compounds to bind to any estrogen receptors, ERα, ERβ or GPER, and act subsequently inside or outside the nucleus as signaling molecules, independently of whether the final cellular responses is the regulation of transcriptional activity or any other cellular event.”

The authors further review scientific studies demonstrating the importance of these mechanisms in EDC actions observed in beta-cells in the pancreas (diabetes-relevant effects) and in cardiomyocytes in the heart (cardiovascular disease-relevant effects).


Nadal, A., et al. (2017). “Extranuclear-initiated estrogenic actions of endocrine disrupting chemicals: Is there toxicology beyond Paracelsus?The Journal of Steroid Biochemistry and Molecular Biology (published online January 31,2017).