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