Estrogen Receptor-α Knockout Mice Exhibit Resistance to the Developmental Effects of Neonatal Diethylstilbestrol Exposure on the Female Reproductive Tract (original) (raw)

2001, Developmental Biology

Data indicate that estrogen-dependent and -independent pathways are involved in the teratogenic/carcinogenic syndrome that follows developmental exposure to 17␤-estradiol or diethylstilbestrol (DES), a synthetic estrogen. However, the exact role and extent to which each pathway contributes to the resulting pathology remain unknown. We employed the ␣ERKO mouse, which lacks estrogen receptor-␣ (ER␣), to discern the role of ER␣ and estrogen signaling in mediating the effects of neonatal DES exposure. The ␣ERKO provides the potential to expose DES actions mediated by the second known ER, ER␤, and those that are ER-independent. Wild-type and ␣ERKO females were treated with vehicle or DES (2 g/pup/day for Days 1-5) and terminated after 5 days and 2, 4, 8, 12, and 20 months for biochemical and histomorphological analyses. Assays for uterine expression of the genes Hoxa10, Hoxa11, and Wnt7a shortly after treatment indicated significant decreases in DES-treated wild-type but no effect in the ␣ERKO. In contrast, the DES effect on uterine expression of Wnt4 and Wnt5a was preserved in both genotypes, suggesting a developmental role for ER␤. Adult ␣ERKO mice exhibited complete resistance to the chronic effects of neonatal DES exposure exhibited in treated wild-type animals, including atrophy, decreased weight, smooth muscle disorganization, and epithelial squamous metaplasia in the uterus; proliferative lesions of the oviduct; and persistent vaginal cornification. Therefore, the lack of DES effects on gene expression and tissue differentiation in the ␣ERKO provides unequivocal evidence of an obligatory role for ER␣ in mediating the detrimental actions of neonatal DES exposure in the murine reproductive tract.