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However, the paternal developmental origins of PPP remain poorly understood. Using a rat model, we found that paternal preconception caffeine exposure (PPCE) induced PPP\u2010like phenotypes in female offspring and showed paternal\u2010line persistence to the F2 generation. Mechanistic analyses showed that PPCE induced a paternal glucocorticoid\u2010elevated state and was associated with hypermethylation of the\n                    <jats:italic>Gnas<\/jats:italic>\n                    imprinting control region (ICR) in sperm. In offspring ovaries, this alteration was paralleled by increased\n                    <jats:italic>Gnas<\/jats:italic>\n                    \u2010ICR methylation, reduced Nespas expression, increased Gnas expression, activation of the cAMP\/PKA\/CREB pathway and enhanced estrogen biosynthesis. Ovarian Gnas gain\u2010 and loss\u2010of\u2010function experiments supported a functional contribution of Gnas dysregulation to steroidogenesis and PPP\u2010like phenotypes, while paternal GR antagonism attenuated sperm\/ovarian methylation changes and offspring phenotypes. Exploratory human samples suggested a weak and method\u2010sensitive association between plasma cortisol levels and sperm\n                    <jats:italic>Gnas<\/jats:italic>\n                    \u2010ICR methylation. These findings support a paternal glucocorticoid\u2013associated sperm\n                    <jats:italic>Gnas<\/jats:italic>\n                    \u2010ICR mechanism that may contribute to offspring ovarian endocrine programming. Together, these findings provide a preclinical framework for understanding how paternal preconception endocrine status may shape offspring reproductive development through sperm\u2010associated epigenetic programming.\n                  <\/jats:p>","DOI":"10.1002\/advs.76434","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T12:33:15Z","timestamp":1785241995000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Paternal Sperm\n                    <i>Gnas<\/i>\n                    \u2010ICR Epigenetic Programming Contributes to PPP\u2010Like Phenotypes in Female Offspring"],"prefix":"10.1002","volume":"13","author":[{"given":"Jing","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Gynaecology and Obstetrics Zhongnan Hospital of Wuhan University  Wuhan China"},{"name":"Department of Otorhinolaryngology Head and Neck Surgery Zhongnan Hospital of Wuhan University  Wuhan China"},{"name":"Provincial Key Laboratory of Developmentally Originated Disease  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Basic Medical School of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7383-178X","authenticated-orcid":false,"given":"Tiancheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Gynaecology and Obstetrics Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yating","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gynaecology and Obstetrics Zhongnan Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5300-8661","authenticated-orcid":false,"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gynaecology and Obstetrics Zhongnan Hospital of Wuhan University  Wuhan China"},{"name":"Provincial Key Laboratory of Developmentally Originated Disease  Wuhan China"},{"name":"Department of Pharmacology Basic Medical School of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecl.2024.01.006"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-4642(23)00237-7"},{"key":"e_1_2_12_4_1","volume-title":"StatPearls","author":"Sharma 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