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To test this hypothesis, we employed <jats:italic>Lhcgr<\/jats:italic>\n              <jats:sup>W495X\/+<\/jats:sup> (luteinizing hormone\/chorionic gonadotropin receptor) male mice subjected to prenatal Di-(2-ethylhexyl) phthalate (DEHP) exposure, a model designed to investigate steroidogenic gene expression in gene-environment interactions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Pregnant wild-type (WT) dams (mated with <jats:italic>Lhcgr<\/jats:italic>\n              <jats:sup>W495X\/+<\/jats:sup> heterozygote (HET) received varying levels of DEHP: no exposure, low-dose (100\u00a0mg\/kg\/d) DEHP, and high-dose (1000\u00a0mg\/kg\/d) DEHP during gestation, which led to prenatal exposure in male offspring. Male offspring were divided into HET (<jats:italic>Lhcgr<\/jats:italic>\n              <jats:sup>W495X\/+<\/jats:sup>) and WT groups based on genotype in three levels of DEHP exposure. The study assessed phenotypic characteristics (DSD, testosterone levels, and semen quality) and examined the expression of steroidogenic genes (<jats:italic>Lhcgr<\/jats:italic>,<jats:italic> Star<\/jats:italic>,<jats:italic> Cyp11a1<\/jats:italic>,<jats:italic> Cyp17a1<\/jats:italic>,<jats:italic> Hsd17b3<\/jats:italic>, and <jats:italic>Hsd3b2<\/jats:italic>).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>\n              <jats:italic>Lhcgr<\/jats:italic>\n              <jats:sup>W495X\/+<\/jats:sup> male offspring without DEHP exposure exhibited normal phenotypes and steroidogenic gene profiles. Low-dose DEHP had no detectable effects on WT offspring, but synergistically induced DSD in <jats:italic>Lhcgr<\/jats:italic>\n              <jats:sup>W495X\/+<\/jats:sup> male offspring by interfering with steroidogenic gene expression (<jats:italic>Lhcgr<\/jats:italic>,<jats:italic> Hsd17b3<\/jats:italic>,<jats:italic> Hsd3b2<\/jats:italic>). High-dose DEHP caused DSD in both genotypes, but the severity of DSD and interference with steroidogenic gene expression were more pronounced in <jats:italic>Lhcgr<\/jats:italic>\n              <jats:sup>W495X\/+<\/jats:sup> male offspring.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This study verifies that Genetic variants (<jats:italic>Lhcgr<\/jats:italic>\n              <jats:sup>W495X\/+<\/jats:sup>) and environmental toxicants (DEHP) synergistically induce DSD, thereby elucidating the pathogenesis of DSD. Interfering with steroidogenic gene expression may be an important synergistical mechanism. This finding highlights the clinical imperative to minimize prenatal exposure to endocrine disruptors, particularly in pregnancies with variants of DSD.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13293-025-00753-0","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T10:41:58Z","timestamp":1758883318000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic variants (LhcgrW495X\/+) and environmental toxicants (DEHP) synergistically induce DSD by interfering with steroidogenic gene expression"],"prefix":"10.1186","volume":"16","author":[{"given":"Xie","family":"Qigen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Kai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cao","family":"Haiming","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Zhe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gao","family":"Yong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deng","family":"Chunhua","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,9,26]]},"reference":[{"key":"753_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1136\/adc.2006.098319","volume":"91","author":"IA Hughes","year":"2006","unstructured":"Hughes IA, Houk C, Ahmed SF, Lee PA. 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