{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:22:48Z","timestamp":1792156968994,"version":"4.4.0"},"reference-count":64,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T00:00:00Z","timestamp":1629158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The University of Wisconsin Office of Vice Chancellor for Graduate and Research Education","award":["Fall Competition Award"],"award-info":[{"award-number":["Fall Competition Award"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T35OD011078"],"award-info":[{"award-number":["T35OD011078"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Tamoxifen is an estrogen receptor (ER) ligand with widespread use in clinical and basic research settings. Beyond its application in treating ER-positive cancer, tamoxifen has been co-opted into a powerful approach for temporal-specific genetic alteration. The use of tamoxifen-inducible Cre-recombinase mouse models to examine genetic, molecular, and cellular mechanisms of development and disease is now prevalent in biomedical research. Understanding off-target effects of tamoxifen will inform its use in both clinical and basic research applications. Here, we show that prenatal tamoxifen exposure can cause structural birth defects in the mouse. Administration of a single 200 mg\/kg tamoxifen dose to pregnant wildtype C57BL\/6J mice at gestational day 9.75 caused cleft palate and limb malformations in the fetuses, including posterior digit duplication, reduction, or fusion. These malformations were highly penetrant and consistent across independent chemical manufacturers. As opposed to 200 mg\/kg, a single dose of 50 mg\/kg tamoxifen at the same developmental stage did not result in overt structural malformations. Demonstrating that prenatal tamoxifen exposure at a specific time point causes dose-dependent developmental abnormalities, these findings argue for more considerate application of tamoxifen in Cre-inducible systems and further investigation of tamoxifen\u2019s mechanisms of action.<\/jats:p>","DOI":"10.1371\/journal.pone.0256299","type":"journal-article","created":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T18:22:13Z","timestamp":1629224533000},"page":"e0256299","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":25,"title":["Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse"],"prefix":"10.1371","volume":"16","author":[{"given":"Miranda R.","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin C.","family":"Steward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma A.","family":"Sweet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1994-4090","authenticated-orcid":true,"given":"Robert J.","family":"Lipinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,8,17]]},"reference":[{"issue":"1","key":"pone.0256299.ref001","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1006\/meth.2001.1159","article-title":"Site- and time-specific gene targeting in the mouse","volume":"24","author":"D Metzger","year":"2001","journal-title":"Methods"},{"issue":"5","key":"pone.0256299.ref002","article-title":"Abnormal Reproductive Development in Rats After Neonatally Administered Antiestrogen (Tamoxifen)","volume":"21","year":"1979","journal-title":"Biology of reproduction"},{"issue":"1","key":"pone.0256299.ref003","article-title":"Occurrence of Genital Tract Abnormalities and Bladder Hernia in Female Mice Exposed Neonatally to Tamoxifen","volume":"42","year":"1986","journal-title":"Toxicology"},{"issue":"11","key":"pone.0256299.ref004","article-title":"Teratogenic Effects of Clomiphene, Tamoxifen, and Diethylstilbestrol on the Developing Human Female Genital Tract","volume":"18","year":"1987","journal-title":"Human pathology"},{"issue":"1","key":"pone.0256299.ref005","article-title":"Maternal Exposure to Tamoxifen During Pregnancy Increases Carcinogen-Induced Mammary Tumorigenesis Among Female Rat Offspring","volume":"6","year":"2000","journal-title":"Clinical cancer research: an official journal of the American Association for Cancer Research"},{"issue":"2","key":"pone.0256299.ref006","article-title":"Maternal Tamoxifen Treatment Alters Oocyte Differentiation in the Neonatal Mice: Inhibition of Oocyte Development and Decreased Folliculogenesis","volume":"36","year":"2010","journal-title":"The journal of obstetrics and gynaecology research"},{"issue":"10","key":"pone.0256299.ref007","article-title":"Proliferative Lesions of Oviduct and Uterus in CD-1 Mice Exposed Prenatally to Tamoxifen","volume":"18","year":"1997","journal-title":"Carcinogenesis"},{"key":"pone.0256299.ref008","author":"N Ved","journal-title":"Tamoxifen administration in pregnant mice can be deleterious to both mother and embryo"},{"key":"pone.0256299.ref009","first-page":"1547","article-title":"Use of Tamoxifen Before and During Pregnancy","author":"G Braems","journal-title":"Oncologist"},{"key":"pone.0256299.ref010","unstructured":"Tewari K, Perinatology Division DoOaG, Women\u2019s Hospital, Memorial Medical Center, Long Beach, California, and Division of Pediatric Urology and Urologic Oncology DoU, University of California, Bonebrake RG, Perinatology Division DoOaG, Women\u2019s Hospital, Memorial Medical Center, Long Beach, California, and Division of Pediatric Urology and Urologic Oncology DoU, University of California, et al. Ambiguous genitalia in infant exposed to tamoxifen in utero. Elsevier, 1997 1997\/07\/19. Report No.: 1474-547X Contract No.: 9072."},{"issue":"1","key":"pone.0256299.ref011","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.bjoms.2020.07.009","article-title":"Tamoxifen exposure induces cleft palate in mice","volume":"59","author":"J Xu","year":"2021","journal-title":"Br J Oral Maxillofac Surg"},{"issue":"6","key":"pone.0256299.ref012","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1161\/CIRCRESAHA.120.317025","article-title":"Tamoxifen-Activated CreERT Impairs Retinal Angiogenesis Independently of Gene Deletion","volume":"127","author":"JT Brash","year":"2020","journal-title":"Circ Res"},{"issue":"7","key":"pone.0256299.ref013","article-title":"Confounding factors from inducible systems for spatiotemporal gene expression regulation","volume":"219","author":"RCI W\u00fcst","year":"2020","journal-title":"J Cell 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