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However, the impact of paternal pre\u2010pregnant caffeine exposure (PPCE) on offspring health remains unexplored. This study elucidates the sperm reprogramming mechanism and potential intervention targets for PPCE\u2010induced non\u2010alcoholic steatohepatitis (NASH) in offspring. Here, male rats are administrated caffeine (15\u201360\u00a0mg\u00a0kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    \/d) by gavage for 8 weeks and then mated with females to produce offspring. This study finds that NASH with transgenerational inheritance occurred in PPCE adult offspring. Mechanistically, a reduction of miR\u2010142\u20103p is implicated in the occurrence of NASH, characterized by hepatic lipid metabolism dysfunction and chronic inflammation through an increase in ACSL4. Conversely, overexpression of miR\u2010142\u20103p mitigated these manifestations. The origin of reduced miR\u2010142\u20103p levels is traced to hypermethylation in the miR\u2010142\u20103p promoter region of parental sperm, induced by elevated corticosterone levels rather than by caffeine per se. Similar outcomes are confirmed in offspring conceived via in vitro fertilization using miR\u2010142\u20103p\n                    <jats:sup>KO<\/jats:sup>\n                    sperm. Overall, this study provides the first evidence of transgenerational inheritance of NASH in PPCE offspring and identifies miR\u2010142\u20103p as a potential therapeutic target for NASH induced by paternal environmental adversities.\n                  <\/jats:p>","DOI":"10.1002\/advs.202405592","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T05:10:15Z","timestamp":1726636215000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Sperm miR\u2010142\u20103p Reprogramming Mediates Paternal Pre\u2010Pregnancy Caffeine Exposure\u2010Induced Non\u2010Alcoholic Steatohepatitis in Male Offspring Rats"],"prefix":"10.1002","volume":"11","author":[{"given":"Cong","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Basic Medical Sciences Wuhan University  Wuhan 430071 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