Multi-omics analysis elucidates the mechanisms of As-induced toxicity in mouse GCs

Arsenic (As) is a prevalent environmental contaminant known to cause damage to the female ovaries and granulosa cells (GCs), with unclear molecular mechanisms. In this study, an As-induced mouse injury model, characterized of decreased numbers of ovarian GCs and litter sizes, was established through intraperitoneal injection of NaAsO2 (8 mg/kg body weight), and a multi-omics strategy was conducted to evaluate the influence of As on mice ovarian. Through multi-omics network analysis, it was found that As not only induced DNA breakage by down-regulating the transcriptional levels of Mapk15 and Wee2, but also decreased the expression of DNA repair-related proteins such as PARP1, XRCC1 and PNKP. Concurrently, As caused cell cycle arrest via inhibiting the expression of cell-cycle related proteins. Moreover, As induced apoptosis of GCs through activating the MAPK pathway. Notably, As significantly increased phospho-protein kinase A substrate (p-PKAs) levels and activated histone deacetylases, resulting in reduced levels of acetylation modification of H3K9, H3K14, H4K5, and H4K8 histones, potentially contributing to the ovarian GCs toxicity. Overall, the study provides important insights into the potential mechanisms underlying As-induced toxicity in females and highlights the need for continued research to fully understand the implications for As-induced health risks.