Estrogen receptor ESR1 is indispensable for the induction of persistent vaginal change by neonatal 5alpha-dihydrotestosterone exposure in mice

Development of the reproductive organs can be strongly affected by the hormonal environment. In the mouse, exposure to estrogens and androgens during the critical developmental period induces estrogen-independent cell proliferation and differentiation in the adult vaginal epithelium, which often results in cancerous lesions later in life. In the present study, we assessed the contributions of estrogen receptor 1 (alpha) (ESR1) to the developmental effects of the nonaromatizable androgen 5alpha-dihydrotestosterone (DHT) on female mouse vagina and external genitalia. The vagina of Esr1^-/- mice treated neonatally with DHT showed atrophic epithelium, whereas the vaginal epithelium of Esr1^+/+ mice was stratified and keratinized even after ovariectomy. In addition, neonatal treatment with DHT led to persistent phosphorylation of ESR1 in the vaginae of 60-day-old ovariectomized mice. We infer from these data that ESR1 is obligatory for the induction and maintenance of persistent vaginal epithelial changes induced by neonatal administration of DHT. Neonatal DHT treatment also induced hypospadias in both Esr1^-/- and Esr1^+/+ mice. In contrast, DHT-induced formation of an os penis-like large bone in the clitoris was found in Esr1^-/- mice but not in Esr1^+/- or Esr1^+/+ mice. These results shed light on mechanisms of the induction of developmental effects elicited by sex steroid hormones on the developing animals.