Triazole fungicides are highly effective pesticides widely used in plant protection, which has caused potential hazards to human health and ecological safety. To fully understand their potential hepatotoxicity, we first analyzed the transcriptome profiles in HepG2 cells treated with five triazole fungicides (hexiconazole (HEX), tebuconazole (TEB), propiconazole (PRO), cyproconazole (CYP), and difenoconazole (DIF)), and found that these pesticides remarkably affected estrogen signaling pathways, especially estrogen synthesis. Furthermore, we found that TEB, CYP, PRO and DIF had agonistic activity towards estrogen receptor alpha (ERα) and elucidated the binding mode of triazole ligands with ERα using the reporter gene assay and molecular docking. Four triazole fungicides regulated eight major genes involved in estrogen synthesis (StAR, CYP11A1, 3βHSD2, CYP17, CYP19, CYP3A4, CYP1A2 and SCP2) and stimulated the secretion of 17β-estradiol (E₂). Finally, we assessed possible metabolic outcomes caused by abnormal estrogen synthesis, and found that triazole fungicides affected the metabolism of various macromolecules (such as lipid, amino acid, and carbohydrate) and signal transduction. These findings will provide new insights into endocrine-disrupting effects of triazole fungicides and highlight their potential ecological and health risks.

三唑类杀菌剂是一种广泛应用于植物保护的高效农药，对人体健康和生态安全造成了潜在危害。为了充分了解它们的潜在肝毒性，我们首先分析了用五种三唑类杀菌剂（己康唑 (HEX)、戊唑醇 (TEB)、丙环唑 (PRO)、环丙康唑 (CYP) 和苯醚甲环唑 (DIF)）处理的 HepG2 细胞中的转录组谱，以及发现这些农药显着影响雌激素信号通路，尤其是雌激素合成。此外，我们发现TEB、CYP、PRO和DIF对雌激素受体α（ERα）具有激动活性，并通过报告基因分析和分子对接阐明了三唑配体与ERα的结合模式。四种三唑类杀菌剂调节参与雌激素合成的八个主要基因（Star, CYP11A1, 3βHSD2, CYP17, CYP19, CYP3A4, CYP1A2和SCP2 ) 并刺激 17β-雌二醇 (E ₂ ) 的分泌。最后，我们评估了雌激素合成异常可能导致的代谢结果，发现三唑类杀菌剂影响各种大分子（如脂质、氨基酸和碳水化合物）的代谢和信号转导。这些发现将为三唑类杀菌剂的内分泌干扰作用提供新的见解，并突出其潜在的生态和健康风险。