This study evaluated the effects of Cl₃BPA on kisspeptin-G-protein coupled receptor 54 (GPR54)/gonadotropin-releasing hormone (GnRH) (KGG) signals and analyzed the roles of estrogen receptor alpha (ERɑ) and G-protein coupled estrogen receptor 1 (GPER1) in regulating KGG signals. The results showed that Cl₃BPA at 50 μM increased the levels of intracellular reactive oxygen species (ROS) and GnRH, upregulated the protein levels of kisspeptin and the expression of fshr, lhr and gnrh1 genes related to KGG in GT1-7 cells. In addition, 50 μM Cl₃BPA significantly upregulated the phosphorylation of extracellular regulated protein kinases 1/2 (Erk1/2), the protein levels of GPER1 and the expression of the gper1 as well as the most target genes associated with mitogen-activated protein kinase (MAPK)/Erk1/2 pathways. Specific signal inhibitor experiments found that Cl₃BPA activated KGG signals by activating the GPER1-mediated MAPK/Erk1/2 signaling pathway at the mRNA level. A docking test further confirmed the interactions between Cl₃BPA and GPER1. The findings suggest that Cl₃BPA might induce precocious puberty by increasing GnRH secretion together with KGG signaling upregulation, which is driven by GPER1-mediated signaling pathway. By comparison, Cl_xBPAs with fewer chlorine atoms had more obvious effects on the expression of proteins and partial genes related to KGG signals in GT1-7 cells.

本研究评估了 Cl ₃ BPA 对 Kisspeptin-G-蛋白偶联受体 54 (GPR54)/促性腺激素释放激素 (GnRH) (KGG) 信号的影响，并分析了雌激素受体 α (ERɑ) 和 G-蛋白偶联雌激素的作用受体 1 (GPER1) 调节 KGG 信号。结果显示，50 μM C​​l ₃ BPA 增加 GT1-7 细胞内活性氧（ROS）和 GnRH 水平，上调 Kisspeptin 蛋白水平以及与 KGG 相关的fshr、lhr和gnrh1基因表达。此外，50 μM C​​l ₃ BPA 显着上调细胞外调节蛋白激酶 1/2 (Erk1/2) 的磷酸化、GPER1 的蛋白水平和 gper1以及与丝裂原激活蛋白相关的大多数靶基因的表达。激酶 (MAPK)/Erk1/2 途径。特异性信号抑制剂实验发现，Cl ₃ BPA通过在mRNA水平激活GPER1介导的MAPK/Erk1/2信号通路来激活KGG信号。对接测试进一步证实了Cl ₃ BPA和GPER1之间的相互作用。研究结果表明，Cl ₃ BPA 可能通过增加 GnRH 分泌以及 KGG 信号上调（由 GPER1 介导的信号通路驱动）来诱导性早熟。相比之下，氯原子较少的Cl _x BPA对GT1-7细胞中与KGG信号相关的蛋白质和部分基因的表达有更明显的影响。