Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, PR China.
South China Institute of Environmental Sciences, Ministry of Environmental Protection of the People's Republic of China, State Environmental Protection Key Laboratory of Environmental Pollution Health Risk Assessment, Guangzhou, Guangdong Province 510530, PR China.
Ecotoxicol Environ Saf. 2022 Mar 15;233:113290. doi: 10.1016/j.ecoenv.2022.113290. Epub 2022 Feb 12.
Chlorobisphenol A (ClBPA) is a kind of novel estrogenic compounds. The present study aims to investigate the effects of three ClBPA 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 ClBPA 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, ClBPA activated nuclear estrogen receptor alpha (ERα) 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 ERα inhibitor ICI reduced the expression of KissR1, GnRH1 and kisspeptin proteins, attenuated mRNA levels of Kiss1, GnRH1, KissR1, Fshr and Lhr genes, and decreased ClBPA-induced GT1-7 cell proliferation. The results suggested that ClBPA activated the KGG neuroendocrine signals and induced the proliferation of GT1-7 cells via ERα and GPER signaling pathways. This study provides a new perspective to explore the neuroendocrine toxicity mechanism of ClBPA. CAPSULE: ClBPA activated KGG neuroendocrine signaling pathway via ERα and GPER and induced the proliferation of GT1-7 cells.
氯双酚 A（ClBPA）是一种新型雌激素化合物。本研究旨在通过雌激素受体信号通路，探讨三种 ClBPA 化合物对神经元 GT1-7 细胞 kisspeptin/G 蛋白偶联受体 54（GPR54，也称为 KissR1-促性腺激素释放激素（GnRH）（KGG）系统的影响，揭示其作用机制。研究表明，低浓度 ClBPA 诱导细胞增殖，促进 GnRH 分泌，上调 KGG 神经内分泌信号相关蛋白（KissR1、GnRH1 和 kisspeptin）和 Kiss1、GnRH1、KissR1、促黄体生成素受体（Lhr）和卵泡刺激素受体（Fshr）等基因的表达。此外，ClBPA 激活核雌激素受体α（ERα）和成员雌激素受体 G 蛋白偶联雌激素受体（GPER）调节的磷脂酰肌醇-3-激酶/蛋白激酶 B（PI3K/Akt）和细胞外信号调节激酶（Erk1/2）信号通路。用 GPER 抑制剂 G15 和 ERα 抑制剂 ICI 预处理 GT1-7 细胞，可降低 KissR1、GnRH1 和 kisspeptin 蛋白的表达，减弱 Kiss1、GnRH1、KissR1、Fshr 和 Lhr 基因的 mRNA 水平，并减弱 ClBPA 诱导的 GT1-7 细胞增殖。结果表明，ClBPA 通过 ERα 和 GPER 信号通路激活 KGG 神经内分泌信号，诱导 GT1-7 细胞增殖。本研究为探讨 ClBPA 的神经内分泌毒性机制提供了新视角。
