Background Polychlorinated biphenyls (PCBs) are persistent pollutants with carcinogenesis and mutagenesis effects which have been closely associated with PCBs-induced DNA damage. However, the detailed DNA damage events and corresponding pathway alterations under PCBs poisoning is still not well understood. Methods Whole-genome sequencing (WGS) and RNA sequencing (RNA-seq) were used to explore genome wide variations and related pathway changes in HEK293T cells that challenged by 15 µM PCB153 for 96 h in vitro. Double strand breaks (DSBs) were measured by 53BP1 foci detection, altered pathways were confirmed by quantitative real-time PCR (qPCR). Results The results indicated that abundant copy number variations (CNVs), including four duplications and 30 deletions, occurred in PCB153-exposed HEK293T cells. Multiple large fragment deletions (>1 Mb) involving up to 245 Mb regions on many chromosomes. Missense mutations were found in six tumor susceptibility genes, two of which are key members participating in homologous recombination (HR) repair response, BRCA1 and BRCA2. RNA-seq data showed that PCB153 poisoning apparently suppressedHR repairing genes. Besides, 15 µM PCB153 exposure significantly increased 53BP1 foci formation and effectively reduced BRCA1, RAD51B and RAD51C expression, indicating an elevated DSBs and impaired HR repairing. Conclusion This study firstly reported multiple large chromosomal deletions and impaired HR repairing in PCB153-exposed HEK293T cells, which provided a new insight into the understanding of early response and the mechanism underlying PCB153 genotoxicity. The chromosomal instabilities might be related to the impaired HR repairing that induced by PCB153; however, further investigations, especially on actual toxic effects of human body, are needed to confirm such speculation.

中文翻译：

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暴露于多氯联苯 153 的 HEK293T 细胞中的大染色体缺失和同源重组修复受损

背景多氯联苯（PCBs）是一种具有致癌和诱变作用的持久性污染物，与PCBs诱导的DNA损伤密切相关。然而，在多氯联苯中毒下，详细的 DNA 损伤事件和相应的通路改变仍不清楚。方法 采用全基因组测序（WGS）和RNA测序（RNA-seq）在体外探索15 µM PCB153 96 h攻击HEK293T细胞的全基因组变异和相关通路变化。通过 53BP1 病灶检测测量双链断裂 (DSB)，通过定量实时 PCR (qPCR) 确认改变的途径。结果结果表明，PCB153暴露的HEK293T细胞中存在丰富的拷贝数变异（CNVs），包括4个重复和30个缺失。多个大片段删除（> 1 Mb) 涉及许多染色体上多达 245 Mb 的区域。在六个肿瘤易感基因中发现了错义突变，其中两个是参与同源重组 (HR) 修复反应的关键成员，BRCA1 和 BRCA2。RNA-seq数据显示PCB153中毒明显抑制了HR修复基因。此外，15 µM PCB153 暴露显着增加 53BP1 病灶形成并有效降低 BRCA1、RAD51B 和 RAD51C 表达，表明 DSB 升高和 HR 修复受损。结论 本研究首次报道了暴露于 PCB153 的 HEK293T 细胞中的多个大染色体缺失和 HR 修复受损，这为理解早期反应和 PCB153 基因毒性的潜在机制提供了新的见解。染色体不稳定可能与PCB153诱导的HR修复受损有关；然而，需要进一步调查，特别是对人体的实际毒性影响，以证实这种猜测。