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Ethinyl Estradiol: Evaluating the Effects of a Model Estrogen Receptor Agonist on the Adult Male Mouse
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Abstract
Ethinyl estradiol (EE2) is a pharmaceutical estrogen receptor (ER) agonist and estrogen mimic commonly used in birth control and hormone replacement therapy. Pharmaceutical estrogen is also taken at high levels by trans women undergoing gender-affirming hormone therapy (GAHT) to promote breast growth and other feminizing characteristics. With increasing pharmaceutical use, EE2 contamination in wastewater and groundwater is a growing environmental concern. There is evidence that the male mammary gland is highly responsive to ER agonist exposure during sensitive windows of development, but whether the adult male mammary gland is a strong model for studying estrogenic exposures remains to be seen. In this study, we evaluate the physiological and endocrine-disrupting effects of exposure to EE2 in adult male mice at a range of doses: Low EE2 (1 μg/kg/day), representative of environmental exposures in wastewater, Mid EE2 (10 μg/kg/day) as a mid-range dose, and High EE2 (100 μg/kg/day), representative of estrogen prescribed to trans women undergoing GAHT. Exposures occurred orally through drinking water and lasted for 8 weeks. Chronic exposure to Mid and High doses of EE2 in drinking water caused significant deficits in body weight of adult male mice and altered the size of several organs, indicating toxic effects. Mid and High EE2-exposed males also had larger and more complex mammary glands compared to controls, with epithelial structures structurally and histologically similar to female terminal end buds (TEBs). This study shows that long-term High EE2 exposure in adult male mice induces mammary epithelium with morphology comparable to female mammary glands during puberty. Additionally, the lack of significant effects of Low EE2 exposure on the adult male mammary gland in this study indicates that the male mammary gland may only be an effective screening model for estrogenic chemicals if exposures occur during sensitive windows of development.
Type
Thesis (Open Access)
Date
2025-05
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Embargo Lift Date
2026-05-16