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Although past research predominantly focused on individual phthalates, real-life human exposure typically encompasses complex mixtures of these compounds. The cumulative effects of prolonged exposure to phthalate mixtures on uterine health remain poorly understood. To address this knowledge gap, we conducted studies utilizing adult female mice exposed chronically to a mixture of phthalates for 12\u2009mo through ad libitum chow consumption. Our studies revealed that continuous exposure to this phthalate mixture led to uterine hyperplasia with a significant increase in gland-to-stroma ratio. Endometrial hyperplasia is commonly caused by heightened estrogenic action and inflammatory response in the uterus, leading to increased proliferation of endometrial epithelial cells. Indeed, we observed a marked upregulation of several known estrogen-regulated genes, proinflammatory chemokines, elevated homing of macrophages, and increased KI67 staining in the endometrial epithelial cells upon phthalate exposure. Several signaling pathways, including the MAPK\/ERK and Wnt\/\u03b2-Catenin pathways, promote cell proliferation, leading to the hyperproliferative state of the endometrial cells. Our studies revealed no alteration of the MAPK\/ERK pathway but a marked enhancement of the Wnt\/\u03b2-Catenin signaling pathway in phthalate-exposed uteri. Collectively, this study underscores the significance of understanding the exposure to environmental factors in the pathogenesis of endometrial disorders.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaf062","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T14:49:47Z","timestamp":1746456587000},"page":"58-67","source":"Crossref","is-referenced-by-count":7,"title":["Exposure to phthalates enhances estrogen and beta-catenin signaling pathways, leading to endometrial\u00a0hyperplasia in mice"],"prefix":"10.1093","volume":"206","author":[{"given":"Ritwik","family":"Shukla","sequence":"first","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois at Urbana-Champaign , Urbana, IL 61802,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5889-8157","authenticated-orcid":false,"given":"Athilakshmi","family":"Kannan","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois at Urbana-Champaign , Urbana, IL 61802,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary J","family":"Laws","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois at Urbana-Champaign , Urbana, IL 61802,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Wagoner Johnson","sequence":"additional","affiliation":[{"name":"Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign , Urbana, IL 61801,","place":["United States"]},{"name":"Carle R. 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Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign , Urbana, IL 61801,","place":["United States"]},{"name":"Department of Biomedical and Translational Sciences, Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign , Urbana, IL 61801,","place":["United States"]},{"name":"Department of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign , Urbana, IL 61801,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indrani C","family":"Bagchi","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois at Urbana-Champaign , Urbana, IL 61802,","place":["United States"]},{"name":"Carle R. 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