Metabolic dysfunction and genomic instability are known to affect female fertility. Aroclor 1254 (A1254) is an endocrine disruptor that affects mitochondrial function following ingestion, inhalation, or dermal exposure. Numerous studies to date have addressed associations between A1254 toxicity and chronic neurological disorders, while A1254 exposure is little known to have a toxic effect on the female reproductive system. Furthermore, interactive mechanisms between metabolic dysfunction and the repair of DNA damage deserve further investigation. In this paper, an in vitro porcine primary granulosa cell (GC) culture model was used to investigate the mechanisms of exposure and effects of the exogenous chemical carcinogen A1254 on reproductive toxicology. High-throughput RNA sequencing obtained 2329 differentially expressed genes (DEGs) to be analyzed using COG classification, GO, and KEGG. When combined with immunofluorescence, Western blot analysis, and real-time RT-PCR analysis, this data showed that the mitochondrial-ROS-driven feed-forward loop increased phospho-PDGFRα/β, which stimulates apoptosis by suppressing the PI3K-Akt pathway. We also noticed that inhibition of the Akt-PDP1-PDK1 axis attenuated mitochondrial function. In contrast, following iPath analysis, partial metabolic pathways were enhanced. Importantly, we found that A1254 activated a DNA damage response, the major regulators of which belong to the PI3K-related protein kinases (PIKKs) and oncogenes, which led to the "Warburg effect". It is not easy to restore the damage that A1254 causes to metabolism through dysregulation and the Warburg effect, owing to the fact that oncogenes can regulate cytoplasmic metabolism. Therefore, we suspect that the PDGFR-PI3K-Akt pathway may be a latent interaction between mitochondrial dysfunction and the response of DNA damage.

中文翻译：

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PDGFRα/β-PI3K-Akt途径对Aroclor 1254暴露的猪颗粒细胞中线粒体功能障碍和DNA损伤相互作用的响应。

代谢功能障碍和基因组不稳定会影响女性的生育能力。Aroclor 1254（A1254）是一种内分泌干扰物，在摄入，吸入或皮肤接触后会影响线粒体功能。迄今为止，许多研究已经解决了A1254毒性与慢性神经系统疾病之间的关联，而鲜为人知的是A1254暴露对女性生殖系统有毒性作用。此外，代谢功能障碍与DNA损伤修复之间的相互作用机制值得进一步研究。本文采用体外猪原代颗粒细胞（GC）培养模型，研究外源化学致癌物A1254的暴露机理及其对生殖毒理学的影响。高通量RNA测序获得了2329个差异表达基因（DEG），将使用COG分类，GO和KEGG进行分析。当与免疫荧光，蛋白质印迹分析和实时RT-PCR分析结合使用时，该数据表明线粒体ROS驱动的前馈环增加了磷酸-PDGFRα/β，从而通过抑制PI3K-Akt途径刺激了细胞凋亡。我们还注意到抑制Akt-PDP1-PDK1轴减弱了线粒体功能。相反，在iPath分析之后，部分代谢途径得以增强。重要的是，我们发现A1254激活了DNA损伤反应，其主要调节子属于PI3K相关蛋白激酶（PIKKs）和致癌基因，从而导致“ Warburg效应”。由于致癌基因可以调节细胞质代谢，因此通过失调和Warburg效应来恢复A1254对代谢造成的损害并不容易。因此，我们怀疑PDGFR-PI3K-Akt途径可能是线粒体功能障碍与DNA损伤反应之间的潜在相互作用。