Recent evidence indicates that PM poses a risk for congenital heart diseases but the mechanisms remain unclear. We hypothesized that AHR activated by PM might cause mitochondrial damage via PGC-1α dysregulation, leading to heart defects. We initially discovered that the PGC-1α activator ZLN005 counteracted cardiac defects in zebrafish larvae exposed to EOM (extractable organic matter) from PM. Moreover, ZLN005 attenuated EOM-induced PGC-1α downregulation, mitochondrial dysfunction/biogenesis, and apoptosis. EOM exposure not only decreased PGC-1α expression levels, but suppressed its activity via deacetylation, and SIRT1 activity is required during both processes. We then found that SIRT1 expression levels and NAD/NADH ratio were reduced in an AHR-dependent way. We also demonstrated that AHR directly suppressed the transcription of SIRT1 while promoted the transcription of TiPARP which consumed NAD. In conclusion, our study suggests that PM induces mitochondrial damage and heart defects via AHR/SIRT1/PGC-1α signal pathway.

中文翻译：

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PM2.5通过AHR-SIRT1-PGC-1α介导的线粒体损伤诱导心脏缺陷

最近的证据表明 PM 会带来先天性心脏病的风险，但其机制仍不清楚。我们假设 PM 激活的 AHR 可能会通过 PGC-1α 失调导致线粒体损伤，从而导致心脏缺陷。我们最初发现 PGC-1α 激活剂 ZLN005 可以抵消暴露于 PM 中的 EOM（可提取有机物）的斑马鱼幼虫的心脏缺陷。此外，ZLN005 还可减弱 EOM 诱导的 PGC-1α 下调、线粒体功能障碍/生物发生和细胞凋亡。EOM 暴露不仅降低了 PGC-1α 的表达水平，还通过脱乙酰化抑制了其活性，而 SIRT1 活性在这两个过程中都是必需的。然后我们发现 SIRT1 表达水平和 NAD/NADH 比率以 AHR 依赖性方式降低。我们还证明AHR直接抑制SIRT1的转录，同时促进消耗NAD的TiPARP的转录。总之，我们的研究表明 PM 通过 AHR/SIRT1/PGC-1α 信号通路诱导线粒体损伤和心脏缺陷。