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 esr2a blocked TDMPP-induced liver impairments, which was further confirmed in the esr2a-/- mutant line. Subsequently, transcriptomic analysis showed that the estrogen receptor activated by TDMPP inhibited the expression of smc2, which was linked to the suppression of liver development through p53 activation. Consistently, overexpression of smc2 and inhibition of p53 evidently rescued hepatic damages induced by TDMPP. Taken together, the above findings identified esr2a, downstream smc2, and p53 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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雌激素受体 2a 的 TDMPP 激活调节 SMC2 和 p53 信号传导，以干扰斑马鱼的肝脏发育 （Danio rerio）


磷酸三（2,6-二甲基苯基）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。雌激素在肝脏发育过程中调节各种生物反应中至关重要。然而，TDMPP 对斑马鱼肝脏发育的影响在很大程度上仍未得到探索。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作用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损伤，包括肝脏大小减小、组织病理学变化和肝细胞凋亡。此外，E2 引起的不良反应与 TDMPP 相似，但雌激素合成的药物阻断减轻了对肝脏发育的影响。化学抑制剂和吗啉代敲低测定表明，esr2a 的减少阻断了 TDMPP 诱导的肝损伤，这在 esr2a-/-突变系中得到了进一步证实。随后，转录组学分析显示，TDMPP 激活的雌激素受体抑制 smc2 的表达，这与通过 p53 激活抑制肝脏发育有关。一致地，smc2 的过表达和 p53 的抑制显然挽救了 TDMPP 诱导的肝损伤。综上所述，上述发现确定 esr2a 、下游 smc2 和 p53 是 TDMPP 对肝脏发育雌激素作用的重要调节因子。我们的工作填补了目前对 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。 这些发现强调了进一步生态风险评估和监管考虑的必要性。