Beta-cypermethrin (β-CYP) consists of four chiral isomers, acting as an environmental estrogen and causing reproductive toxicity, neurotoxicity, and dysfunctions in multiple organ systems. This study investigated the toxic effects of β-CYP, its isomers, metabolite 3-phenoxybenzoic acid (3-PBA), and 17β-estradiol (E2) on HTR-8/SVneo cells. We focused on the toxic mechanisms of β-CYP and its specific isomers. Our results showed that β-CYP and its isomers inhibit HTR-8/SVneo cell proliferation similarly to E2, with 100 μM 1S-trans-αR displaying significant toxicity after 48 h. Notably, 1S-trans-αR, 1R-trans-αS, and β-CYP were more potent in inducing apoptosis and cell cycle arrest than 1R-cis-αS and 1S-cis-αR at 48 h. AO/EB staining and flow cytometry indicated dose-dependent apoptosis in HTR-8/SVneo cells, particularly at 100 μM 1R-trans-αS. Scratch assays revealed that β-CYP and its isomers variably reduced cell migration. Receptor inhibition assays demonstrated that post-ICI 182780 treatment, which inhibits estrogen receptor α (ERα) or estrogen receptor β (ERβ), β-CYP, its isomers, and E2 reduced HTR-8/SVneo cell viability, whereas milrinone, a phosphodiesterase 3 A (PDE3A) inhibitor, increased viability. Molecular docking studies indicated a higher affinity of β-CYP, its isomers, and E2 for PDE3A than for ERα or ERβ. Consequently, β-CYP, its isomers, and E2 consistently led to decreased cell viability. Transcriptomics and RT-qPCR analyses showed differential expression in treated cells: up-regulation of and , and down-regulation of and , suggesting the PI3K-AKT signaling pathway as a potential route for toxicity. This study aims to provide a comprehensive evaluation of the cytotoxicity of chiral pesticides and their mechanisms.

中文翻译：

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高效氯氰菊酯及其手性异构体对HTR-8/SVneo细胞的毒性作用及机制

高效氯氰菊酯 (β-CYP) 由四种手性异构体组成，作为环境雌激素，可引起生殖毒性、神经毒性和多器官系统功能障碍。本研究研究了 β-CYP、其异构体、代谢物 3-苯氧基苯甲酸 (3-PBA) 和 17β-雌二醇 (E2) 对 HTR-8/SVneo 细胞的毒性作用。我们重点研究 β-CYP 及其特定异构体的毒性机制。我们的结果表明，与 E2 类似，β-CYP 及其异构体抑制 HTR-8/SVneo 细胞增殖，100 μM 1S-trans-αR 在 48 小时后显示出显着的毒性。值得注意的是，48 小时时，1S-trans-αR、1R-trans-αS 和 β-CYP 比 1R-cis-αS 和 1S-cis-αR 更能有效诱导细胞凋亡和细胞周期停滞。AO/EB 染色和流式细胞术表明 HTR-8/SVneo 细胞中的细胞凋亡呈剂量依赖性，特别是在 100 μM 1R-trans-αS 下。划痕试验表明，β-CYP 及其异构体不同程度地减少了细胞迁移。受体抑制测定表明，ICI 182780 后治疗可抑制雌激素受体 α (ERα) 或雌激素受体 β (ERβ)、β-CYP、其异构体和 E2，从而降低 HTR-8/SVneo 细胞活力，而米力农（一种磷酸二酯酶） 3 A (PDE3A) 抑制剂，增加活力。分子对接研究表明，β-CYP、其异构体和 E2 对 PDE3A 的亲和力高于对 ERα 或 ERβ 的亲和力。因此，β-CYP、其异构体和 E2 始终导致细胞活力下降。转录组学和 RT-qPCR 分析显示处理细胞中的差异表达： 和 的上调，以及 和 的下调，表明 PI3K-AKT 信号通路是潜在的毒性途径。本研究旨在对手性农药的细胞毒性及其机制进行综合评价。