Estrogen receptor-α knockout mice exhibit resistance to the developmental effects of neonatal diethylstilbestrol exposure on the female reproductive tract

Data indicate that estrogen-dependent and -independent pathways are involved in the teratogenic/carcinogenic syndrome that follows developmental exposure to 17 beta -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 alpha ERKO mouse, which lacks estrogen receptor-alpha (ER alpha)(r). to discern the role of ER alpha and estrogen signaling in mediating the effects of neonatal DES exposure. The aERKO provides the potential to expose DES actions mediated by the second known ER, ER beta, and those that are ER-independent. Wild-type and alpha ERKO females were treated with vehicle or DES (2 mug/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 alpha ERKO. In contrast, the DES effect on uterine expression of Wnt4 and Wnt5a was preserved in both genotypes, suggesting a developmental role for ER beta. Adult aERKO 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 alpha ERKO provides unequivocal evidence of, an obligatory role for ERa in mediating the detrimental actions of neonatal DES exposure in the murine reproductive tract. (C) 2001 Academic Press.