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However, the precise mechanisms underlying the impact of gestational environmental stress on fetal testicular development require further investigation. This study demonstrates that gestational environmental stressor cadmium exposure caused placental estradiol synthesis inhibition and fetal testicular dysplasia. Gestational estradiol supplementation restores fetal testicular dysplasia caused by environmental stress\u2010induced placental estradiol synthesis inhibition. Analysis of human placentae and cadmium\u2010stimulated human primary placental trophoblasts confirmed that ER\u2010phagy is associated with the inhibition of estradiol synthesis in placentae. Subsequently, the data reveals that environmental stress significantly activates RTN3L\u2010mediated ER\u2010phagy.\n                    <jats:italic>RTN3L<\/jats:italic>\n                    \u2010deficient cells and placental\n                    <jats:italic>Rtn3l<\/jats:italic>\n                    \u2010specific knockout mice confirm that environmental stress\u2010activated RTN3L\u2010mediated ER\u2010phagy inhibited placental estradiol synthesis. Total N6\u2010methyladenosine level increasing in gestational environmental stress\u2010exposed placentae. METTL3\u2010mediated N6\u2010methyladenosine modification suppression obviously restrains environmental stress\u2010activated RTN3L\u2010dependent ER\u2010phagy. In conclusion, gestational environmental stress activates ER\u2010phagy by increasing placental\n                    <jats:italic>Rtn3l<\/jats:italic>\n                    mRNA N6\u2010methyladenosine modification, inhibiting placental estradiol synthesis, and contributing to fetal testicular dysplasia. The study demonstrates the early prevention and treatment of adult male infertility from the perspective of fetal\u2010derived diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202500924","type":"journal-article","created":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T06:02:58Z","timestamp":1745647378000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Placental RTN3L\u2010dependent ER\u2010Phagy Contributes to Fetal Testicular Dysplasia Upon Environmental Stress"],"prefix":"10.1002","volume":"12","author":[{"given":"Ye\u2010Xin","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Toxicology Center for Big Data and Population Health of IHM School of Public Health Anhui Medical University  Hefei 230022 China"},{"name":"Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes  Hefei 230022 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