Estrogen receptor-alpha 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 involve d in the teratogenic/carcinogenic syndrome that follows developmental expos ure 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, w hich lacks estrogen receptor-alpha (ER alpha)(r). to discern the role of ER alpha and estrogen signaling in mediating the effects of neonatal DES expo sure. The aERKO provides the potential to expose DES actions mediated by th e second known ER, ER beta, and those that are ER-independent. Wild-type an d alpha ERKO females were treated with vehicle or DES (2 mug/pup/day for Da ys 1-5) and terminated after 5 days and 2, 4, 8, 12, and 20 months for bioc hemical and histomorphological analyses. Assays for uterine expression of t he genes Hoxa10, Hoxa11, and Wnt7a shortly after treatment indicated signif icant decreases in DES-treated wild-type but no effect in the alpha ERKO. I n contrast, the DES effect on uterine expression of Wnt4 and Wnt5a was pres erved in both genotypes, suggesting a developmental role for ER beta. Adult aERKO mice exhibited complete resistance to the chronic effects of neonata l DES exposure exhibited in treated wild-type animals, including atrophy, d ecreased weight, smooth muscle disorganization, and epithelial squamous met aplasia in the uterus; proliferative lesions of the oviduct; and persistent vaginal cornification. Therefore, the lack of DES effects on gene expressi on and tissue differentiation in the alpha ERKO provides unequivocal eviden ce of, an obligatory role for ERa in mediating the detrimental actions of n eonatal DES exposure in the murine reproductive tract. (C) 2001 Academic Pr ess.