Key Laboratory of Human Genetics and Environmental Medicine, Key Laboratory of Environment and Health, School of Public Health, Xuzhou Medical University, Xuzhou, China.
School of Nursing, Jilin University, Changchun, China.
J Hazard Mater. 2024 Sep 15;477:135379. doi: 10.1016/j.jhazmat.2024.135379. Epub 2024 Jul 31.
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.
三（2,6-二甲基苯基）磷酸酯（TDMPP）是一种新型的有机磷阻燃剂（OPFR），已被发现具有雌激素活性。雌激素在肝脏发育过程中对各种生物反应的调节至关重要。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效应，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 0.5μM）的斑马鱼幼虫表现出浓度依赖性的肝脏损伤，包括肝体积减小、组织病理学变化和肝细胞凋亡。此外，E2 对 TDMPP 也产生了类似的不良影响，但雌激素合成的药理学阻断缓解了对肝脏发育的影响。化学抑制剂和莫洛尼寡核苷酸敲低试验表明，esr2a 的减少阻断了 TDMPP 诱导的肝脏损伤，这在 esr2a-/-突变体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了 smc2 的表达，这通过 p53 激活与肝脏发育的抑制有关。一致地，smc2 的过表达和 p53 的抑制明显挽救了 TDMPP 诱导的肝损伤。综上所述，上述发现确定了 esr2a、下游的 smc2 和 p53 是 TDMPP 对肝脏发育的雌激素效应的重要调节因子。我们的工作填补了 TDMPP 肝毒性的现有知识中的关键空白，为 TDMPP 的不良影响和作用机制提供了新的见解。这些发现强调了需要进一步进行生态风险评估和监管考虑。
