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.
Subject(s)
Cleft Palate/etiology , Limb Deformities, Congenital/etiology , Maternal Exposure/adverse effects , Prenatal Exposure Delayed Effects/chemically induced , Tamoxifen/toxicity , Teratogens/toxicity , Animals , Cleft Palate/pathology , Dose-Response Relationship, Drug , Female , Fetus , Gene Expression , Humans , Integrases/genetics , Integrases/metabolism , Limb Deformities, Congenital/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pregnancy , Prenatal Exposure Delayed Effects/pathology , Selective Estrogen Receptor ModulatorsABSTRACT
OBJECTIVE: Gender demographics vary across specialties including surgery, internal medicine, cardiology, neurology, and oncology. Our objective was to determine whether residency selection or the decision to apply for training drives these differences. STUDY DESIGN: Retrospective cohort study. SAMPLE POPULATION: Matched and unmatched residents lists from Veterinary Internship and Residency Matching Program (VIRMP) from 2011 to 2020. Comparative Data Reports from the American Association of Veterinary Medical Colleges from 2010 to 2019. METHODS: Names for matched and unmatched residents with addresses in the United States or Canada were coded for gender for seven programs: large and small animal surgery, large and small animal medicine, cardiology, neurology, and oncology. Match rate by gender was compared using chi-square tests. Gender demographics of applicants were compared to demographics of graduates using tests of two proportions. RESULTS: No differences were observed between genders for the likelihood of successfully matching into each residency program evaluated except in large animal internal medicine. Women (44.2%) were slightly more likely to match, overall, than men (39.0%, p = .003). The proportions of women applying for residencies overall (70.7%), in large and small animal surgery (66.1%, 62.2%), cardiology (70.2%), and neurology (70.7%) were lower than the proportion of female graduates (79%; p's < .001). CONCLUSION: No evidence for gender bias was detected in the VIRMP resident selection process. Female veterinary graduates seemed less likely to apply for residencies than their male counterparts. IMPACT: Occupational segregation seems to stem from the decision to apply for residency. Interventions aimed at altering gender demographics in specialized medicine should target potential applicants.
