{"id":149,"title":"Paternal zearalenone exposure impairs transgenerational male spermatogenesis via the METTL14-m6A-Thap1-glutathione axis","title_zh":"父系玉米赤霉烯酮暴露经 METTL14-m6A-Thap1-谷胱甘肽轴跨代损害雄性精子发生","url":"https://pubmed.ncbi.nlm.nih.gov/42988297","doi":"10.1016/j.envres.2026.126119","pmid":"42988297","journal":"Environ Res","kind":"paper","lang":"en","published_at":"2026-11-05T00:00:00+00:00","fetched_at":"2026-11-08T03:43:57+00:00","authors":["Chen C","Ren YT","Lin S","Hu XY","Wei YN","Liu JR","Wang R","Chen YH"],"primary_topic":"male","topics":[{"slug":"male","score":8.0,"hits":["male infertility","sperm","spermatogenesis","testes","testicular"]},{"slug":"repro-genetics","score":4.0,"hits":["transgenerational"]},{"slug":"repro-tox","score":2.0,"hits":["endocrine-disrupting","reproductive toxicity"]},{"slug":"art-clinical","score":1.0,"hits":["infertility"]},{"slug":"omics-methods","score":1.0,"hits":["multi-omics"]}],"topic_score":8.0,"preference_score":10.0,"preference_labels":["多组学整合分析（任意生殖对象）"],"llm_score":86.0,"final_score":96.0,"score_dims":{"novelty":88,"rigor":80,"impact":82,"relevance":92,"translation":72},"recommend_reason":"首次将环境霉菌毒素的父系跨代生殖毒性串联到METTL14-m6A-YTHDF2-THAP1-GSH这一完整表观转录组机制，并以敲低/过表达双向验证，对男性生殖毒理与表观遗传研究均有直接参考价值。","keywords":["玉米赤霉烯酮","跨代遗传","m6A","METTL14","精子发生","谷胱甘肽"],"selected":1,"story_id":57,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"pubmed-gametes","source_name":"PubMed · 配子与性腺","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":null,"journal_tier":"unknown","journal_if":null,"is_mock":false,"summary_zh":"本研究在小鼠中给予父代慢性玉米赤霉烯酮暴露（5 mg/kg/日，10周），发现F1与F2代雄性后代精子计数与活力下降、畸形率升高、睾丸组织形态受损。多组学分析显示睾丸GSH水平显著降低，源于THAP1转录激活的GSS与GGT7表达下降；父代暴露使Thap1 mRNA候选位点m6A富集增加（由METTL14介导），可能经YTHDF2依赖的降解降低THAP1蛋白。父代睾丸敲低Mettl14或子代睾丸过表达Thap1可恢复GSH与精子发生，提示该表观转录组轴是跨代雄性生殖毒性的机制与潜在干预靶点。","summary":"Zearalenone (ZEA), a widespread mycotoxin with endocrine-disrupting activity, poses a potential risk to male reproduction. However, the transgenerational effects of paternal ZEA exposure on offspring spermatogenesis and the underlying epitranscriptomic mechanisms remain poorly understood. Here, we investigated whether paternal ZEA exposure causes transgenerational male reproductive toxicity and elucidated the associated epitranscriptomic mechanism. In mice, chronic paternal ZEA exposure (5 mg/kg/day for 10 weeks) significantly reduced sperm count and motility, increased the sperm malformation rate, and disrupted testicular histomorphology in F1 and F2 male offspring. Mechanistically, multi-omics analysis revealed a marked reduction in testicular GSH levels. This reduction was attributable to decreased expression of GSS, the terminal enzyme catalyzing the final step of de novo GSH synthesis, and of GGT7, a GSH hydrolase involved in GSH degradation/recycling; both enzymes are transcriptionally activated by THAP1. Notably, paternal ZEA exposure is associated with increased METTL14-mediated m6A enrichment at candidate sites of Thap1 mRNA, which may promote YTHDF2-dependent decay and reduce THAP1 protein. Knockdown of Mettl14 in paternal testes or targeted overexpression of Thap1 in offspring testes rescued GSH levels, restored spermatogenesis, and alleviated reproductive impairment. Collectively, our findings identify a previously unrecognized epitranscriptional mechanism by which paternal ZEA exposure transmits reproductive toxicity across generations via the METTL14-m6A-Thap1-GSH axis, providing a potential target for intervention against mycotoxin-induced male infertility.","interpretation_basis":null,"fulltext_status":"not_found","interpretation":null,"fulltext":{"available":false,"status":"not_found","reason":"Europe PMC 无此记录：DOI 10.1016/j.envres.2026.126119","pmcid":null,"license":null,"chars":0,"source":"Europe PMC","fetched_at":"2026-11-08T03:59:08+00:00"}}