Chlorobisphenol A activated kisspeptin/GPR54-GnRH neuroendocrine signals through ERα and GPER pathway in neuronal GT1-7 cells

Chlorobisphenol A (Cl(x)BPA) is a kind of novel estrogenic compounds. The present study aims to investigate the effects of three Cl(x)BPA compounds on the kisspeptin/G protein-coupled receptor 54 (GPR54, also named KissR1)-gonadotropin-releasing hormone (GnRH) (KGG) system in neuronal GT1-7 cells with mechanistic insights by estrogen receptor signaling pathways. The study demonstrated that low-concentration Cl(x)BPA induced the cell proliferation, promoted GnRH secretion, upregulated the expression of KGG neuroendocrine signal-related proteins (KissR1, GnRH1 and kisspeptin) and genes including Kiss1, GnRH1, KissR1, luteinizing hormone receptor (Lhr) and follicle-stimulating hormone receptor (Fshr) in GT1-7 cells. Additionally, Cl(x)BPA activated nuclear estrogen receptor alpha (ER alpha) and member estrogen receptor G protein-coupled estrogen receptor (GPER)regulated phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinase (Erk1/2) signaling pathways. Pretreatment of GT1-7 cells with GPER inhibitor G15 and ER alpha inhibitor ICI reduced the expression of KissR1, GnRH1 and kisspeptin proteins, attenuated mRNA levels of Kiss1, GnRH1, KissR1, Fshr and Lhr genes, and decreased Cl(x)BPA-induced GT1-7 cell proliferation. The results suggested that Cl(x)BPA activated the KGG neuroendocrine signals and induced the proliferation of GT1-7 cells via ER alpha and GPER signaling pathways. This study provides a new perspective to explore the neuroendocrine toxicity mechanism of Cl(x)BPA. Capsule: Cl(x)BPA activated KGG neuroendocrine signaling pathway via ER alpha and GPER and induced the proliferation of GT1-7 cells.

Automated summary

This study investigated the effects of Cl(x)BPA compounds on the KGG system in neuronal cells and found that Cl(x)BPA activates the KGG neuroendocrine signaling pathway via ER alpha and GPER, leading to cell proliferation.