Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse.

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-recombin...

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Autores principales:	Miranda R Sun, Austin C Steward, Emma A Sweet, Alexander A Martin, Robert J Lipinski
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8b17ba8695694a41b57d7cab74fb038c
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spelling	oai:doaj.org-article:8b17ba8695694a41b57d7cab74fb038c2021-12-02T20:17:59ZDevelopmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse.1932-620310.1371/journal.pone.0256299https://doaj.org/article/8b17ba8695694a41b57d7cab74fb038c2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0256299https://doaj.org/toc/1932-6203Tamoxifen 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's mechanisms of action.Miranda R SunAustin C StewardEmma A SweetAlexander A MartinRobert J LipinskiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 8, p e0256299 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Miranda R Sun Austin C Steward Emma A Sweet Alexander A Martin Robert J Lipinski Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse.
description	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's mechanisms of action.
format	article
author	Miranda R Sun Austin C Steward Emma A Sweet Alexander A Martin Robert J Lipinski
author_facet	Miranda R Sun Austin C Steward Emma A Sweet Alexander A Martin Robert J Lipinski
author_sort	Miranda R Sun
title	Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse.
title_short	Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse.
title_full	Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse.
title_fullStr	Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse.
title_full_unstemmed	Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse.
title_sort	developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/8b17ba8695694a41b57d7cab74fb038c
work_keys_str_mv	AT mirandarsun developmentalmalformationsresultingfromhighdosematernaltamoxifenexposureinthemouse AT austincsteward developmentalmalformationsresultingfromhighdosematernaltamoxifenexposureinthemouse AT emmaasweet developmentalmalformationsresultingfromhighdosematernaltamoxifenexposureinthemouse AT alexanderamartin developmentalmalformationsresultingfromhighdosematernaltamoxifenexposureinthemouse AT robertjlipinski developmentalmalformationsresultingfromhighdosematernaltamoxifenexposureinthemouse
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Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse.

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