Mice lacking membrane estrogen receptor 1 are protected from reproductive pathologies resulting from developmental estrogen exposure†

Abstract

Both membrane and nuclear fractions of estrogen receptor 1 (ESR1) mediate 17β-estradiol (E2) actions. Mice expressing nuclear (n)ESR1 but lacking membrane (m)ESR1 (nuclear-only estrogen receptor 1 [NOER] mice) show reduced E2 responsivity and reproductive abnormalities culminating in adult male and female infertility. Using this model, we investigated whether reproductive pathologies caused by the synthetic estrogen diethylstilbestrol (DES) are mitigated by mESR1 ablation. Homozygous and heterozygous wild-type (WT and HET, respectively) and NOER male and female mice were subcutaneously injected with DES (1 mg/kg body weight [BW]) or vehicle daily from postnatal day (PND) 1–5. Uterine histology was assessed in select DES-treated females at PND 5, whereas others were ovariectomized at PND 60 and treated with E2 (10 μg/kg BW) or vehicle 2 weeks later. Neonatal DES exposure resulted in ovary-independent epithelial proliferation in the vagina and uterus of WT but not NOER females. Neonatal DES treatment also induced ovary-independent adult expression of classical E2-induced transcripts (e.g., lactoferrin [Ltf] and enhancer of zeste homolog 2 [Ezh2]) in WT but not NOER mice. At PND 90, DES-treated WT and HET males showed smaller testes and a high incidence of bacterial pyogranulomatous inflammation encompassing the testes, epididymis and occasionally the ductus deferens with spread to lumbar lymph nodes; such changes were largely absent in NOER males. Results indicate that male and female NOER mice are protected from deleterious effects of neonatal DES, and thus mESR1 signaling is required for adult manifestation of DES-induced reproductive pathologies in both sexes.

Adverse Effects of Plasticizers and Pesticides on Female Reproductive Health

“…Developmental exposure to DES increases proliferation in the developing female rat reproductive tract and abnormal mammary gland morphology; DES induces keratinization of the vaginal epithelium of mice. 13…”

Exogenous Oestrogen Impacts Cell Fate Decision in the Developing Gonads: A Potential Cause of Declining Human Reproductive Health

“…Indeed, in the tammar wallaby, exposure of the developing gonad to oestrogen leads to increased expression of MAP3K1 [163], which lies upstream of ERK1/2 and is a critical regulator of the gonad developmental programs. Mice lacking membrane-bound oestrogen receptors are protected from the impacts of exogenous oestrogens, such as DES [164], demonstrating this rapid response to oestrogen via membrane-bound ERs is likely the major way through which oestrogen impacts gonad development.…”

Diethylstilbestrol Modifies the Structure of Model Membranes and Is Localized Close to the First Carbons of the Fatty Acyl Chains

“…Most interesting is the fact that the effects of DES may be mediated by membrane estrogen receptors. It has been shown that mice genetically engineered to lack membrane estrogen receptors do not suffer pathologies associated with exposure to DES [ 9 ].…”