Benzo[a]pyrene inhibits testosterone biosynthesis via NDUFA10-mediated mitochondrial compromise in mouse Leydig cells: Integrating experimental and in silico toxicological approaches
Benzo[a]pyrene inhibits testosterone biosynthesis via NDUFA10-mediated mitochondrial compromise in mouse Leydig cells: Integrating experimental and in silico toxicological approaches
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苯并[a]芘通过小鼠 Leydig 细胞中 NDUFA10 介导的线粒体损害抑制睾酮生物合成：整合实验和计算机毒理学方法
DOI：
10.1016/j.ecoenv.2022.114075
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发表时间：
2022
影响因子：
6.8
通讯作者：
Lin Ao
中科院分区：
文献类型：
--
作者：
Wang Yang;Haonan Cui;Zili Chai;Peng Zou;Fuquan Shi;Binwei Yang;Guowei Zhang;Huan Yang;Qing Chen;Jinyi Liu;Jia Cao;Xi Ling;Lin Ao
苯并[芘]（B[aP）是多环芳烃（PAH）的代表，在环境中普遍存在，对男性类固醇生成产生有害影响，包括睾酮合成障碍。然而，B[aP 诱导的类固醇生成扰动的确切机制仍然不清楚。在本研究中，我们整合了体内测试、转录组分析、体外测定和联合计算机毒理学方法来描述详细的机制。在小鼠模型中，我们观察到 B[aP 给药显着抑制睾酮合成，并伴有小鼠 Leydig 细胞中线粒体和线粒体吞噬体形成的超微结构损伤。转录组分析表明，B[aP 下调小鼠睾丸中 Ndufa9 、 Ndufa6 、 Ndufa10 和 Ndufa5 的表达，这些基因被确定为参与线粒体复合物 I 组装和功能的关键基因。在体外测试中，生物活性 B[aP 代谢物 BPDE 通过 NDUFA10 介导的线粒体损伤诱导睾酮合成的干扰，而这种干扰进一步加剧TM3 Leydig 细胞中的线粒体自噬。计算机毒理学分析结果与实验观察结果高度一致，并进一步揭示了 B[aP/BPDE 参与的 PPARα 激活可以作为分子起始事件，引发 Ndufa10 表达和睾酮合成的下降。总体而言，我们首次证明 Leydig 细胞中的线粒体受损是 B[aP 诱导的类固醇生成扰动中极其重要的目标。 • B[aP 诱导的线粒体损伤抑制 Leydig 细胞中睾酮的合成。 • 线粒体自噬会加剧 B[aP 诱导的线粒体损伤和睾酮水平下降。 • NDUFA10 参与 B[aP 介导的复合物 Ⅰ 和类固醇生成的损害。 • B[aP 激活的 PPARα 引发 NDUFA10 表达和类固醇生成下降。
Benzo[apyrene (B[aP), a representative of polycyclic aromatic hydrocarbons (PAHs), is ubiquitously spread in the environment and showing deleterious impacts on male steroidogenesis, including testosterone synthesis disorder. However, the precise mechanisms involved in B[aP-induced steroidogenesis perturbation remains obscure. In the present study, we integrated in vivo tests, transcriptome profiling, in vitro assays, and conjoint in silico toxicological approaches to delineate the detailed mechanisms. In mouse models, we observed that B[aP administration remarkably inhibited testosterone synthesis accompanied by ultrastructural impairments of mitochondria and mitophagosome formation in mouse Leydig cells. Transcriptome profiling showed that B[aP down-regulated the expression of Ndufa9 , Ndufa6 , Ndufa10 , and Ndufa5 in mouse testes, which are identified as critical genes involved in the assembly and functionality of mitochondrial complex I. In the in vitro tests, the bioactive B[aP metabolite BPDE induced perturbation of testosterone synthesis by NDUFA10-mediated mitochondrial impairment, which was further exacerbated by mitophagy in TM3 Leydig cells. The findings of in silico toxicological analyses were highly consistent with the experimental observations and further unveiled that B[aP/BPDE-involved PPARα activation could serve as a molecular initiating event to trigger the decline in Ndufa10 expression and testosterone synthesis. Overall, we have shown the first evidence that mitochondrial compromise in Leydig cells is the extremely crucial target in B[aP-induced steroidogenesis perturbation. • B[aP-induced mitochondrial damage inhibits testosterone synthesis in Leydig cells. • Mitophagy exacerbates B[aP-induced mitochondrial damage and decline in testosterone. • NDUFA10 participates in B[aP-mediated impairment of complex Ⅰ and steroidogenesis. • B[aP-activated PPARα triggers declines in NDUFA10 expression and steroidogenesis.