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Estrogen Actions in the Male Reproductive System Involve Estrogen Response Element-Independent Pathways

Department of Medicine (J.W., M.L.B., M.M.L., L.A.H., C.G.K., S.P., M.T., J.L.J.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; and Receptor Biology Section (K.K.), Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: J. Larry Jameson, M.D., Ph.D., Northwestern University Feinberg School of Medicine, Medical Dean’s Administration, Morton 4-656, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: ljameson{at}northwestern.edu.

The estrogen receptor- (ER) acts through multiple pathways, including estrogen response element (ERE)-dependent (classical) and ERE-independent (nonclassical) mechanisms. We previously created a mouse model harboring a two-amino-acid mutation of the DNA-binding domain (E207A, G208A) that precludes direct binding of ER to an ERE. After crossing heterozygous mutant mice with an ER knockout (ERKO) line, it was possible to assess the degree of physiological rescue by the isolated ER nonclassical allele (–/AA; AA) when compared with ERKO mice (–/–) and to wild type (+/+; WT). In male ERKO mice up to 8 months of age, testosterone levels were high, although LH levels were similar to WT. Testosterone was normal in the AA mice, indicating that the AA allele rescues the enhanced testosterone biosynthesis in ERKO mice. Male ERKO mice exhibited distention of the seminiferous tubules as early as 2–3 months of age as a consequence of decreased water resorption in the efferent ducts. By 3–4 months of age, ERKO mice had impaired spermatogenesis in approximately 40% of their tubules, and sperm counts and motility declined in association with the histological changes. In the AA mice, histological defects were greatly reduced or absent, and sperm counts and motility were rescued. Levels of aquaporins 1 and 9, which contribute to water uptake in the efferent ducts, were reduced in ERKO mice and partially or fully rescued in AA mice, whereas another water transporter, sodium-hydrogen exchanger-3, was decreased in both ERKO and AA mice. We conclude that non-ERE-dependent estrogen pathways are sufficient to rescue the defective spermatogenesis observed in ERKO mice and play a prominent role in ER action in the testis, including pathways that regulate water resorption and androgen biosynthesis.

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