Center for Global Health, China International Cooperation Center for Environment and Human Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; Suzhou Center for Disease Control and Prevention, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Suzhou, 215004, Jiangsu, People's Republic of China.
Center for Global Health, China International Cooperation Center for Environment and Human Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China.
Environ Pollut. 2022 Nov 15;313:120090. doi: 10.1016/j.envpol.2022.120090. Epub 2022 Sep 2.
Studies have demonstrated that arsenic (As) induces male reproductive injury, however, the mechanism remains unknown. The high levels of arsenic (3) methyltransferase (As3MT) promote As-induced male reproductive toxicity. For As-exposed mice, the germ cells in seminiferous tubules and sperm quality were reduced. Exposure to As caused lower S-adenosylmethionine (SAM) and 5-methylcytosine (5 mC) levels, histone and DNA hypomethylation, upregulation of long interspersed element class 1 (LINE1, or L1), defective repair of double-strand breaks (DSBs), and the arrest of meiosis, resulting in apoptosis of germ cells and lower litter size. For GC-2spd (GC-2) cells, As induced apoptosis, which was prevented by adding SAM or by reducing the expression of As3MT. The levels of LINE1, affected by SAM content, were involved in As-induced apoptosis. Furthermore, folic acid (FA) and vitamin B12 (VB) supplements restored SAM, 5 mC, and LINE1 levels and blocked impairment of spermatogenesis and testes and lower litter size. Exposed to As, mice with As3MT knockdown showed less impairment of spermatogenesis and testes and greater litter size compared to As-exposed wild-type (WT) mice. Thus, the high As3MT levels induced by As consume SAM and block histone and LINE1 DNA methylation, elevating LINE1 expression and evoking impairment of spermatogenesis, which causes male reproductive damage. Overall, we have found a mechanism for As-induced male reproductive damage, which provides biological insights into the alleviation of reproductive injury induced by environmental factors.
研究表明，砷（As）会导致雄性生殖损伤，但具体机制尚不清楚。高浓度的砷（III）甲基转移酶（As3MT）可促进砷诱导的雄性生殖毒性。对于接触砷的小鼠，生精小管中的生殖细胞和精子质量减少。砷暴露导致 S-腺苷甲硫氨酸（SAM）和 5-甲基胞嘧啶（5mC）水平降低，组蛋白和 DNA 低甲基化，长散布元件 1（LINE1，或 L1）上调，双链断裂（DSBs）修复缺陷，减数分裂停滞，导致生殖细胞凋亡和产仔数减少。对于 GC-2spd（GC-2）细胞，砷诱导细胞凋亡，添加 SAM 或降低 As3MT 表达可预防细胞凋亡。受 SAM 含量影响的 LINE1 水平参与了砷诱导的细胞凋亡。此外，叶酸（FA）和维生素 B12（VB）补充剂可恢复 SAM、5mC 和 LINE1 水平，并阻断精子发生和睾丸损伤以及产仔数减少。与接触砷的野生型（WT）小鼠相比，敲低 As3MT 的小鼠的精子发生和睾丸损伤减少，产仔数增加。因此，砷诱导的高 As3MT 水平消耗 SAM 并阻断组蛋白和 LINE1 DNA 甲基化，导致 LINE1 表达升高，引发精子发生损伤，导致雄性生殖损伤。总之，我们发现了砷诱导雄性生殖损伤的机制，为环境因素引起的生殖损伤的缓解提供了生物学见解。
