南京中医药大学学报2026，Vol.42Issue(8)：1174-1184,11.DOI:10.14148/j.issn.1672-0482.2026.1174
联合ATAC-seq和RNA-seq探究无机砷诱导小鼠雄性生殖损伤的作用机制
Exploring the Mechanisms of Inorganic Arsenic-Induced Male Reproductive Damage in Mice via Integrated ATAC-seq and RNA-seq Analysis
摘要
Abstract
OBJECTIVE To investigate the effects of inorganic arsenic(iAs)exposure on male reproductive function in mice and to elucidate the underlying epigenetic regulatory mechanisms at the levels of chromatin accessibility and gene expression.METHODS Six-week-old male ICR mice were used to establish a subchronic iAs exposure model via drinking water.The mice were divided into four groups:control(tap water),low dose(5 mg·L⁻¹ NaAsO₂),medium dose(25 mg·L⁻¹ NaAsO₂),and high dose(125 mg·L⁻¹ NaAsO₂).Samples were collected at 12 and 20 weeks of exposure.Testicular histopathology,sperm quality,serum hormone levels,and tissue ar-senic content were measured.Testes from the 20-week high-dose group and the control group were subjected to ATAC-seq and RNA-seq;integrated analysis was performed to identify key regulatory genes.The expression of key genes was validated in TM3 and TM4 cells.RESULTS iAs exposure induced abnormal testicular architecture,reduced sperm motility,decreased sperm density,increased sperm deformity rate,and lowered serum testosterone levels in mice,with damage intensifying with prolonged exposure duration and in-creased dose.ATAC-seq revealed iAs exposure induced genome-wide chromatin remodeling.RNA-seq showed that downregulated genes were enriched in spermatogenesis,mitochondrial oxidative phosphorylation,and blood-testis barrier pathways,while upregulated genes were enriched in epigenetic regulatory pathways such as histone H3K4 methylation.Integrated analysis identified histone H3K4 methyltransferase genes(Kmt2a,Kmt2c,Kmt2d,Kmt2e,Ash1l,Setd1b)and spermatogenesis-related genes(Sox5,Rarb,Diaph3,Tdrkh,Tssk6).Cellular experiments confirmed that iAs exposure upregulated histone H3K4 methyltransferases and their downstream chroma-tin remodeling factors in TM4 Sertoli cells.CONCLUSION Subchronic iAs exposure can induce male reproductive impairment in mice.Aberrant upregulation of histone H3K4 methyltransferases and their downstream chromatin remodeling factors represents one of the key molecular mechanisms underlying iAs-mediated male reproductive damage.关键词
无机砷/雄性生殖毒性/ATAC-seq/RNA-seq/染色质可及性/组蛋白H3K4甲基化Key words
inorganic arsenic/male reproductive toxicity/ATAC-seq/RNA-seq/chromatin accessibility/histone H3K4 methylation分类
医药卫生引用本文复制引用
焦佳铭,应晓栋,丰一然,肖波,杨宁,王超杰,任雪峰,陈栩燊..联合ATAC-seq和RNA-seq探究无机砷诱导小鼠雄性生殖损伤的作用机制[J].南京中医药大学学报,2026,42(8):1174-1184,11.基金项目
浙江中医药大学研究生科学研究基金项目(Y202456376) （Y202456376）
