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Exposure during development to non-mutagenic environmental factors can contribute to cancer risk, but the underlying mechanisms are not understood. We used a mouse model of endometrial adenocarcinoma that results from brief developmental exposure to an estrogenic chemical, diethylstilbestrol (DES), to determine causative factors. Single-cell RNA sequencing (scRNAseq) and spatial transcriptomics of adult control uteri revealed novel markers of uterine epithelial stem cells (EpSCs), identified distinct luminal and glandular progenitor cell (PC) populations, and defined glandular and luminal epithelium (LE) cell differentiation trajectories. Neonatal DES exposure disrupted uterine epithelial cell differentiation, resulting in a failure to generate an EpSC population or distinguishable glandular and luminal progenitors or mature cells. Instead, the DES-exposed epithelial cells were characterized by a single proliferating PC population and widespread activation of Wnt\/\u03b2-catenin signaling. The underlying endometrial stromal cells had dramatic increases in inflammatory signaling pathways and oxidative stress. Together, these changes activated phosphoinositide 3-kinase\/AKT serine-threonine kinase signaling and malignant transformation of cells that were marked by phospho-AKT and the cancer-associated protein olfactomedin 4. Here, we defined a mechanistic pathway from developmental exposure to an endocrine disrupting chemical to the development of adult-onset cancer. These findings provide an explanation for how human cancers, which are often associated with abnormal activation of PI3K\/AKT signaling, could result from exposure to environmental insults during development.<\/jats:p>","DOI":"10.1371\/journal.pbio.3002334","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T13:22:33Z","timestamp":1697721753000},"page":"e3002334","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":29,"title":["Developmental estrogen exposure in mice disrupts uterine epithelial cell differentiation and causes adenocarcinoma via Wnt\/\u03b2-catenin and PI3K\/AKT signaling"],"prefix":"10.1371","volume":"21","author":[{"given":"Elizabeth","family":"Padilla-Banks","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy N.","family":"Jefferson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian N.","family":"Papas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa A.","family":"Suen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana V.","family":"Carreon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia J.","family":"Willson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin M.","family":"Quist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-7086","authenticated-orcid":true,"given":"Carmen J.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,10,19]]},"reference":[{"key":"pbio.3002334.ref001","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/nature24271","article-title":"Inflammatory memory sensitizes skin epithelial stem cells to tissue damage","volume":"550","author":"S Naik","year":"2017","journal-title":"Nature"},{"key":"pbio.3002334.ref002","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1126\/science.aae0491","article-title":"The epigenetic landscape of T cell exhaustion","volume":"354","author":"DR Sen","year":"2016","journal-title":"Science"},{"key":"pbio.3002334.ref003","first-page":"91","article-title":"Are poor living conditions in childhood and adolescence an important risk factor for arteriosclerotic heart disease?","volume":"31","author":"A. 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