EXTRANUCLEAR-INITIATED ESTROGENIC ACTIONS OF ENDOCRINE DISRUPTING CHEMICALS: IS THERE TOXICOLOGY BEYOND PARACELSUS?

Publication date: Available online 31 January 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Angel Nadal, Esther Fuentes, Cristina Ripoll, Sabrina Villar-Pazos, Manuel Castellano-Muñoz, Sergi Soriano, Juan Martinez-Pinna, Ivan Quesada, Paloma Alonso-Magdalena
Endocrine Disrupting Chemicals (EDCs), including bisphenol-A (BPA) do not act as traditional toxic chemicals inducing massive cell damage or death in an unspecific manner. EDCs can work upon bind to hormone receptors, acting as agonist, antagonist or modulators. Bisphenol-A displays estrogenic activity and, for many years it has been classified as a weak estrogen, based on the classic transcriptional action of estrogen receptors serving as transcription factors. However, during the last two decades our knowledge about estrogen signaling has advanced considerably. It is now accepted that estrogen receptors ERα and ERβ activate signaling pathways outside the nucleus which may or may not involve transcription. In addition, a new membrane estrogen receptor, GPER, has been proposed. Pharmacological and molecular evidence, along with results obtained in genetically modified mice, demonstrated that BPA, and its substitute BPS, are potent estrogens acting at nanomolar concentrations via extranuclear ERα, ERβ, and GPER. The different signaling pathways activated by BPA and BPS explain the well-known estrogenic effects of low doses of EDCs as well as non-monotonic dose-response relationships. These signaling pathways may help to explain the actions of EDCs with estrogenic activity in the etiology of different pathologies, including type-2 diabetes and obesity.



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