The effects of bisphenol A, benzyl butyl phthalate, and di(2-ethylhexyl) phthalate on estrogen receptor alpha in estrogen receptor-positive cells under hypoxia

Abstract

Endocrine-disrupting chemicals (EDCs) are widely used in various consumer goods. Consequently, humans are constantly exposed to EDCs, which is associated with a variety of endocrine-related diseases. In this study, we demonstrated the effects of bisphenol A (BPA), benzyl butyl phthalate (BBP), and di(2-ethylhexyl) phthalate (DEHP) on estrogen receptor alpha (ERα) expression under normoxia and hypoxia. First, we confirmed the effects of EDCs on ER activity using OECD Test Guideline 455. Compared to the 100% activity induced by 1 nM 17-β-estradiol (positive control), BPA and BBP exhibited 50% ERα activation at concentrations of 1.31 μM and 4.8 μM, respectively. In contrast, and consistent with previous reports, DEHP did not activate ERα. ERα is activated and degraded by hypoxia in breast cancer cells. BPA, BBP, and DEHP enhanced ERα-mediated transcriptional activity under hypoxia. All three EDCs decreased ERα protein levels under hypoxia in MCF-7 cells. The transcriptional activity of hypoxia-inducible factor-1 was decreased and secretion of vascular endothelial growth factor (VEGF) was increased by BPA and BBP under hypoxia in MCF-7 cells, but not by DEHP. All three EDCs decreased the ERα protein expression level in Ishikawa human endometrial adenocarcinoma cells, and DEHP caused a weak decrease in VEGF secretion under hypoxia. These results demonstrate down-regulation of ERα by EDCs may influence the pathological state associated with hypoxia.