Mice lacking membrane‐localized estrogen receptor 1 (mESR1) are partially protected from reproductive pathologies resulting from developmental diethylstilbestrol (DES) 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 abnormalities caused by the synthetic estrogen diethylstilbestrol (DES) are mitigated by mESR1 ablation. To test this, homozygous and heterozygous wild‐type (WT and HET, respectively) male and female mice and NOER mice were subcutaneously injected with DES (1 mg/g BW) or vehicle daily from postnatal day (PND) 1–5. Uterine histology was assessed in select DES‐treated femalesa at PND 5, whereas others were ovariectomized at PND 60 and treated with E2 (10 ng/g BW) or vehicle 2 weeks later. In WT females, DES resulted in ovary‐independentepithelial proliferation in the vagina and uterus. These changes were absent in DES‐treated NOER females. Uterine gene expression paralleled cell proliferation differences with neonatal DES inducing ovary‐independent adult expression of classical E2‐induced transcripts (e.g., Lf, Ezh2) in WT but not NOER mice. Males were examined around PND 90. DES‐treated WT and heterozygous males showed smaller testes and increased incidence of bacterial pyogranulomatous inflammation encompassing the testes, epididymis and in some cases the ductus deferens with spread to lumbar lymph nodes; such changes were largely absent in NOER males. Results indicate 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.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.