Tris (2,6-dimethylphenyl) phosphate (TDMPP), a novel organic phosphorus flame retardant (OPFR), has been found to have estrogenic activity. Estrogens are critical in regulating various biological responses during liver development. However, the effects of TDMPP on zebrafish liver development remain largely unexplored. Here, we utilized a chemical genetic screening approach to assess the estrogenic effects of TDMPP on liver development and to elucidate the underlying molecular mechanism. Our findings revealed that zebrafish larvae exposed to environmentally relevant concentrations of TDMPP (0.05 and 0.5 μM) exhibited concentration-dependent liver impairments, including reduced liver size, histopathological changes, and hepatocyte apoptosis. In addition, E2 caused similar adverse effects to TDMPP, but the pharmacological blockade of estrogen synthesis alleviated the effects on liver development. Chemical inhibitors and morpholino knockdown assays indicated that the reduction of blocked TDMPP-induced liver impairments, which was further confirmed in the mutant line. Subsequently, transcriptomic analysis showed that the estrogen receptor activated by TDMPP inhibited the expression of , which was linked to the suppression of liver development through activation. Consistently, overexpression of and inhibition of evidently rescued hepatic damages induced by TDMPP. Taken together, the above findings identified , downstream , and as important regulators for the estrogenic effects of TDMPP on liver development. Our work fills crucial gaps in the current knowledge of TDMPP's hepatotoxicity, providing new insights into the adverse effects of TDMPP and the molecular mechanisms of action. These findings underscore the need for further ecological risk assessment and regulatory considerations.

中文翻译：

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TDMPP 激活雌激素受体 2a 调节 smc2 和 p53 信号传导，干扰斑马鱼 (Danio rerio) 的肝脏发育


三（2,6-二甲基苯基）磷酸酯（TDMPP）是一种新型有机磷阻燃剂（OPFR），已被发现具有雌激素活性。雌激素对于调节肝脏发育过程中的各种生物反应至关重要。然而，TDMPP 对斑马鱼肝脏发育的影响在很大程度上仍未被探索。在这里，我们利用化学遗传筛选方法来评估 TDMPP 对肝脏发育的雌激素影响并阐明潜在的分子机制。我们的研究结果表明，暴露于环境相关浓度的 TDMPP（0.05 和 0.5 μM）的斑马鱼幼虫表现出浓度依赖性肝脏损伤，包括肝脏尺寸减小、组织病理学变化和肝细胞凋亡。此外，E2引起与TDMPP类似的不良反应，但雌激素合成的药理学阻断减轻了对肝脏发育的影响。化学抑制剂和吗啉敲低测定表明，阻断的 TDMPP 诱导的肝损伤减少，这在突变株系中得到了进一步证实。随后，转录组分析表明，TDMPP 激活的雌激素受体抑制 的表达，这与通过激活抑制肝脏发育有关。一致地，过表达和抑制明显挽救了 TDMPP 诱导的肝损伤。综上所述，上述发现确定了 TDMPP 对肝脏发育的雌激素作用的下游和重要调节因子。我们的工作填补了当前 TDMPP 肝毒性知识的关键空白，为 TDMPP 的不良反应和分子作用机制提供了新的见解。 这些发现强调需要进一步的生态风险评估和监管考虑。