摘要 : Tetrachlorobisphenol A (TCBPA) is the chlorinated derivative of bisphenol A (BPA). Several studies have foundthat BPA adversely affects the reproductive activity largely through binding to estrogen receptors and the criticalperiod... 展开 Tetrachlorobisphenol A (TCBPA) is the chlorinated derivative of bisphenol A (BPA). Several studies have foundthat BPA adversely affects the reproductive activity largely through binding to estrogen receptors and the criticalperiod of BPA exposure advances the vaginal opening time in the female offspring via the kisspeptin/G proteincoupledreceptor 54 (KGG) system. However, whether TCBPA can affect puberty initiation via KGG and the rolesof estrogen receptors in this process remain unknown. Therefore, this study investigated the influence of TCBPAon the onset time of puberty in Wistar rats and the related molecular mechanisms by combing in vitro GT1–7 cellsand molecular docking. In female Wistar rats, TCBPA at ≥100 mg/kg bw/day (49.2 μmol/L in rat body)markedly advanced vaginal opening time and increased serum levels of follicle-stimulating hormone (FSH),luteinizing hormone (LH), and gonadotropin-releasing hormone (GnRH). It also increased the relative geneexpression of LH receptor (LHR), GnRH1, and FSH receptor (FSHR) in hypothalamic-pituitary-gonadal (HPG) axistissues. In GT1–7 cells, TCBPA increased genes and proteins associated with KGG pathway and activated theextracellular-regulated protein kinase 1/2 (Erk1/2) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathways via G protein-coupled estrogen membrane receptor 1 (GPER1) and estrogen receptor alpha (ERα).Docking analyses supported its interactions with GPER1 and ERα, and treatment with specific inhibitors of ERα- and GPER1-modulated PI3K/Akt and Erk1/2 signaling suppressed its effects. Taken together, TCBPA-inducedadvancement of puberty initiation in Wistar rats thus results primarily from increased LH, GnRH, and FSHsecretion together with GnRH1, FSHR, and LHR upregulation driven by ERα- and GPER1-modulated Erk1/2 andPI3K/Akt signaling. Our results provide new molecular insights into the reproductive toxicity of EDCs. 收起