Abstract：
Typical plasticizer di (2-ethylhexyl) phthalate (DEHP) has been demonstrated to induce cardiotoxicity in zebrafish, but the potential molecular mechanisms involved have not been fully elucidated. Aryl hydrocarbon receptor (AhR), an essential protein for inducing developmental abnormalities, has been demonstrated to be activated by DEHP in other species, but whether the AhR signaling pathway also contributes to DEHP-mediated cardiac developmental toxicity in zebrafish remains unclear. Firstly, molecular docking simulations initially confirmed the possibility that DEHP has AhR agonistic activity. To further confirm this conjecture, this work analyzed the changes of cardiac-related indexes in zebrafish stressed by DEHP at individual, protein, and gene levels. The results showed that DEHP mediated cardiac phenotypic developmental defects, increased CYP1A1 activity, and oxidative stress as well as significant changes in the expression levels of key proteins and genes of AhR, Wnt/β-catenin, and Nrf2-Keap1 signaling pathways. Notably, the addition of AhR inhibitors effectively alleviated the above negative effects, indicating that the AhR signaling pathway and its crosstalk with the Wnt/β-catenin signaling pathway is an essential pathway for DEHP-mediated cardiac developmental toxicity. Overall, this work enriches the molecular mechanism of DEHP-mediated cardiac developmental defects in zebrafish and provides a reliable biomarker for future environmental risk assessment of DEHP.
摘要：
典型的增塑剂邻苯二甲酸二（2-乙基己基）酯（DEHP）已被证明在斑马鱼中诱导心脏毒性，但潜在的分子机制尚未完全阐明。芳香烃受体(AhR),一种诱导发育异常的必需蛋白质，已被证明在其他物种中被DEHP激活，但AhR信号通路是否也有助于DEHP介导的斑马鱼心脏发育毒性尚不清楚.首先,分子对接模拟初步证实了DEHP具有AhR激动活性的可能性。为了进一步证实这个猜想,这项工作分析了DEHP胁迫下斑马鱼个体心脏相关指标的变化，蛋白质，和基因水平。结果表明,DEHP介导的心脏表型发育缺陷,CYP1A1活性增加，和氧化应激以及AhR关键蛋白和基因表达水平的显著变化，Wnt/β-catenin,和Nrf2-Keap1信号通路。值得注意的是,添加AhR抑制剂有效缓解了上述负面影响，表明AhR信号通路及其与Wnt/β-catenin信号通路的串扰是DEHP介导的心脏发育毒性的重要通路。总的来说,这项工作丰富了DEHP介导的斑马鱼心脏发育缺陷的分子机制，为未来DEHP的环境风险评估提供了可靠的生物标志物。
