Multi-omics analyses reveal the mechanisms of Arsenic-induced male reproductive toxicity in mice.

Arsenic (As), a widespread environmental contaminant, can induce serious male reproductive injury; however, the underlying mechanisms remain unclear. Multi-omics analyses, including transcriptome, proteome, and phosphoproteome could promote our understanding of As-induced male reproductive toxicity. Here, we established the reproductive injured mice model by intraperitoneal injection of NaAsO2 (8 mg/kg body weight), which was validated by reduced reproductive cells, sperm motility, and litter size. The followed multi-omics analyses of mice revealed that As exposure inhibited ATP production by decreasing the expression of proteins HK1, and GAPDHS, and the enzymatic activities of PDH and SDH. The inhibition of mitochondrial activity and increase in HDAC2 and MTA3 dysregulated the lysine acetylation levels of histone and global proteins. Specifically, the downregulated histones H4K5ac and H4K12ac and upregulated histone H3K9ac disordered the distribution of TP1 to interfere with spermatogenesis. Moreover, As could reduce the expression of COL1A1, RAB13, and LSR to disrupt the junctions between seminiferous tubules, and thereinto, the inhibition of RAB13 increased PKA-dependent phosphorylation. Our study reveals that As causes male reproductive toxicity through decreasing energy production, altering histone acetylation, and impairing cell junctions. Our findings provide basic data for further studies on As reproductive toxicity.