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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370643/ https://www.ncbi.nlm.nih.gov/pubmed/34403436 http://dx.doi.org/10.1371/journal.pone.0256299 |
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author | Sun, Miranda R. Steward, Austin C. Sweet, Emma A. Martin, Alexander A. Lipinski, Robert J. |
author_facet | Sun, Miranda R. Steward, Austin C. Sweet, Emma A. Martin, Alexander A. Lipinski, Robert J. |
author_sort | Sun, Miranda R. |
collection | PubMed |
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 | Online Article Text |
id | pubmed-8370643 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-83706432021-08-18 Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse Sun, Miranda R. Steward, Austin C. Sweet, Emma A. Martin, Alexander A. Lipinski, Robert J. PLoS One Research Article 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. Public Library of Science 2021-08-17 /pmc/articles/PMC8370643/ /pubmed/34403436 http://dx.doi.org/10.1371/journal.pone.0256299 Text en © 2021 Sun et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Sun, Miranda R. Steward, Austin C. Sweet, Emma A. Martin, Alexander A. Lipinski, Robert J. Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse |
title | 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_short | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370643/ https://www.ncbi.nlm.nih.gov/pubmed/34403436 http://dx.doi.org/10.1371/journal.pone.0256299 |
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