Abstract：
The neurotoxicity induced by dioxins has been recognized as a serious concern to sensitive population living near waste incineration plants. However, investigating the intracellular neurotoxicity of dioxin in humans and the corresponding mitigation strategies has been barely studied. Thus, a domestic waste incineration plant was selected in this study to characterize the neurotoxicity risks of sensitive populations by estimating the ratio of dioxin in human cells using membrane structure dynamics simulation; and constructing a complete dioxin neurotoxicity adverse outcome pathway considering the binding process of AhR/ARNT dimer protein and dioxin response element (DRE). Six dioxins with high neurotoxicity risk were identified. According to the composite neurotoxicity risk analysis, the highest composite neurotoxicity risk appeared when the six dioxins were jointly exposed. Dietary schemes were designed using 1/2 partial factor experimental design to mitigate the composite neurotoxicity risk of six dioxins and No. 16 was screened as the optimum combination which can effectively alleviate the composite neurotoxicity risk by 29.52%. Mechanism analysis shows that the interaction between AhR/ARNT dimer protein and DRE was inhibited under the optimal dietary scheme. This study provides theoretical feasibility and reference significance for assessing composite toxicity risks of pollutants and safety mitigation measures for toxic effects.
摘要：
二恶英引起的神经毒性已被认为是生活在垃圾焚烧厂附近的敏感人群的严重关切。然而,研究二恶英在人类中的细胞内神经毒性以及相应的缓解策略几乎没有研究。因此，本研究选择了一家生活垃圾焚烧厂，通过膜结构动力学模拟估计人体细胞中二恶英的比例，以表征敏感人群的神经毒性风险；并考虑AhR/ARNT二聚体蛋白与二恶英反应元件（DRE）的结合过程，构建了完整的二恶英神经毒性不良结局通路。确定了六种具有高神经毒性风险的二恶英。根据复合神经毒性风险分析,当六种二恶英联合暴露时，复合神经毒性风险最高。使用1/2部分因素实验设计饮食方案，以减轻六种二恶英和No.的复合神经毒性风险。筛选出16个组合为可有效减轻复合神经毒性风险29.52%的最佳组合。机制分析表明,在最佳饲粮方案下,AhR/ARNT二聚体蛋白与DRE的相互作用受到抑制。该研究为污染物复合毒性风险评估和毒性效应安全缓解措施提供了理论可行性和参考意义。
