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Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse
Miranda R Sun1, Austin C Steward1, Emma A Sweet1
1Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States of America.
Abstract:
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.
Insights
Prenatal exposure to tamoxifen can cause significant birth defects in mice, including cleft palate and limb malformations. This highlights potential risks of tamoxifen use in research and clinical settings.
Area of Science:
- Developmental biology
- Pharmacology
- Genetics
Background:
- Tamoxifen is a widely used estrogen receptor (ER) ligand in clinical and basic research.
- Tamoxifen-inducible Cre-recombinase mouse models are prevalent for studying development and disease.
- Understanding tamoxifen's off-target effects is crucial for its safe application.
Purpose of the Study:
- To investigate the potential for prenatal tamoxifen exposure to induce structural birth defects in mice.
- To determine the dose-dependency and timing of tamoxifen-induced developmental abnormalities.
Main Methods:
- Administration of tamoxifen to pregnant wildtype C57BL/6J mice at gestational day 9.75.
- Evaluation of fetal development for structural malformations, including cleft palate and limb abnormalities.
- Comparison of different tamoxifen doses (200 mg/kg vs. 50 mg/kg).
Main Results:
- A single 200 mg/kg dose of prenatal tamoxifen caused highly penetrant cleft palate and limb malformations (e.g., digit duplication, reduction, fusion).
- These malformations were consistent across different tamoxifen manufacturers.
- A lower dose of 50 mg/kg tamoxifen did not result in overt structural abnormalities.
Conclusions:
- Prenatal tamoxifen exposure can cause dose-dependent structural birth defects in mice.
- Findings suggest a need for cautious application of tamoxifen in tamoxifen-inducible Cre-recombinase systems.
- Further research into tamoxifen's mechanisms of action is warranted to understand and mitigate developmental risks.
