title: Estrogen receptor-alpha knockout mice exhibit resistance to the developmental effects of neonatal diethylstilbestrol exposure on the female reproductive tract.
abstract: Data indicate that estrogen-dependent and -independent pathways are involved in the teratogenic/carcinogenic syndrome that follows developmental exposure to 17beta-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 alphaERKO mouse, which lacks estrogen receptor-alpha (ERalpha), to discern the role of ERalpha and estrogen signaling in mediating the effects of neonatal DES exposure. The alphaERKO provides the potential to expose DES actions mediated by the second known ER, ERbeta, and those that are ER-independent. Wild-type and alphaERKO females were treated with vehicle or DES (2 microg/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 alphaERKO. In contrast, the DES effect on uterine expression of Wnt4 and Wnt5a was preserved in both genotypes, suggesting a developmental role for ERbeta. Adult alphaERKO 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 alphaERKO provides unequivocal evidence of an obligatory role for ERalpha in mediating the detrimental actions of neonatal DES exposure in the murine reproductive tract.
authors.affiliation: Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. korach@niehs.nih.gov
authors.forename: J F
authors.initials: JF
authors.lastname: Couse
authors.forename: D
authors.initials: D
authors.lastname: Dixon
authors.forename: M
authors.initials: M
authors.lastname: Yates
authors.forename: A B
authors.initials: AB
authors.lastname: Moore
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.forename: R
authors.initials: R
authors.lastname: Maas
authors.forename: K S
authors.initials: KS
authors.lastname: Korach
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000196:embryology / Q000209:etiology*; D000818:Animals; D002454:Cell Differentiation; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004054:Diethylstilbestrol / Q000009:adverse effects*; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D004958:Estradiol / Q000097:blood; D047628:Estrogen Receptor alpha; D005260:Female; D005836:Genitalia, Female / Q000187:drug effects*; D005838:Genotype; D006579:Heterozygote; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000096:biosynthesis; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008431:Maternal-Fetal Exchange; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010057:Oviducts / Q000187:drug effects; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D012313:RNA / Q000378:metabolism; D011863:Radioimmunoassay; D011960:Receptors, Estrogen / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D014594:Uterine Neoplasms / Q000139:chemically induced; D014621:Vagina / Q000187:drug effects; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060528:Wnt4 Protein
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; C484298:HOXA11 protein, human; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C094041:Hoxa11 protein, mouse; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; C555581:WNT4 protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; C490508:Wnt7a protein, mouse; C092119:Hoxa10 protein, mouse; D004958:Estradiol; D012313:RNA; D004054:Diethylstilbestrol; D012260:Ribonucleases