Molecular insights underlying the adverse effects of bisphenol A on gonadal somatic cells' steroidogenic activity
Ewelina Palak1, Weronika Lebiedzinska2, Oana Lupu2
1Department of Biology and Pathology of Human Reproduction, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
Abstract:
Bisphenol A (BPA) exposure may impair gonadal steroidogenesis, although the underlying mechanism is not well known. Hereby, we assessed BPA action on human primary granulosa (hGC) and mouse Leydig cells (BLTK-1) proliferation, cytotoxicity, hormone secretion, and steroidogenic enzyme/receptor gene profile. hGC and BLTK-1 cells were stimulated with increasing concentrations of BPA (10-12 M to 10-4 M for cell proliferation assay, 10-8 M to 10-4 M for LDH-cytotoxicity assay, and 10-9 M to 10-5 M for hormone secretion and genes expression analysis). BPA at low concentrations (pM - nM) did not affect cell proliferation in either cell type, although was toxic at higher (µM) concentrations. BPA stimulation at low nM concentrations decreased the production of estradiol (E2) and testosterone (T) in BLTK-1, E2, and progesterone in hGCs. BPA down-regulated Star, Cyp11a1, and Hsd17b3, but up-regulated Cyp19a1, Esr1, Esr2, and Gpr30 expression in BLTK-1 cells. In hGC, BPA down-regulated STAR, CYP19A1, PGRMC1, and PAQR7 but up-regulated ESR2 expression. Estrogen receptor degrader fulvestrant (FULV) attenuated BPA inhibition of hormone production in both cell lines. FULV also blocked the BPA-induced Gpr30 up-regulation in BLTK-1 cells, whereas in hGC, failed to reverse the down-regulation of PGRMC1, STAR, and CYP19A1. Our findings provide novel mechanistic insights into environmentally-relevant doses of BPA action through both nuclear estrogen receptor-dependent and independent mechanisms affecting cultured granulosa and Leydig cell steroidogenesis.
Insights
Bisphenol A (BPA) impairs steroidogenesis in human granulosa and mouse Leydig cells at environmentally relevant doses. BPA affects hormone production and gene expression via estrogen receptor-dependent and independent pathways.
Area of Science:
- Endocrinology
- Toxicology
- Reproductive Biology
Background:
- Bisphenol A (BPA) is an endocrine-disrupting chemical with potential adverse effects on reproductive health.
- The precise mechanisms by which BPA affects gonadal steroidogenesis remain incompletely understood.
Purpose of the Study:
- To investigate the effects of BPA on the proliferation, cytotoxicity, hormone secretion, and gene expression of steroidogenic enzymes and receptors in human granulosa cells (hGC) and mouse Leydig cells (BLTK-1).
- To elucidate the role of estrogen receptors in mediating BPA's actions on steroidogenesis.
Main Methods:
- Primary hGC and BLTK-1 cells were exposed to varying concentrations of BPA.
- Cell proliferation, cytotoxicity (LDH assay), hormone production (estradiol, testosterone, progesterone), and gene expression (STAR, CYP11A1, HSD17B3, CYP19A1, ESR1, ESR2, GPR30, PGRMC1, PAQR7) were analyzed.
- The effects of the estrogen receptor degrader fulvestrant (FULV) were assessed.
Main Results:
- BPA exhibited cytotoxicity at higher concentrations (µM) but not at lower (pM-nM) levels.
- Low nM concentrations of BPA reduced estradiol, testosterone, and progesterone production.
- BPA altered the expression of key steroidogenic genes and receptors, including down-regulation of STAR, CYP11A1, HSD17B3, PGRMC1, and PAQR7, and up-regulation of CYP19A1, ESR1, ESR2, and GPR30.
- Fulvestrant partially attenuated BPA's inhibitory effects on hormone production and gene expression, indicating both estrogen receptor-dependent and independent mechanisms.
Conclusions:
- Environmentally relevant doses of BPA can disrupt steroidogenesis in human granulosa and mouse Leydig cells.
- BPA exerts its effects through both estrogen receptor-dependent and independent pathways, impacting critical genes involved in hormone synthesis and cellular function.
- These findings provide novel mechanistic insights into the adverse reproductive effects of BPA exposure.
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