title: Estrogen actions in the male reproductive system involve estrogen response element-independent pathways.
abstract: The estrogen receptor-alpha (ERalpha) 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 ERalpha to an ERE. After crossing heterozygous mutant mice with an ERalpha knockout (ERKO) line, it was possible to assess the degree of physiological rescue by the isolated ERalpha 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 ERalpha action in the testis, including pathways that regulate water resorption and androgen biosynthesis.
authors: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors: Jeffrey
authors: J
authors: Weiss
authors: Miranda L
authors: ML
authors: Bernhardt
authors: Monica M
authors: MM
authors: Laronda
authors: Lisa A
authors: LA
authors: Hurley
authors: Christine
authors: C
authors: Glidewell-Kenney
authors: Suresh
authors: S
authors: Pillai
authors: Minghan
authors: M
authors: Tong
authors: Kenneth S
authors: KS
authors: Korach
authors: J Larry
authors: JL
authors: Jameson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology*; D005640:Follicle Stimulating Hormone / Q000097:blood; D007150:Immunohistochemistry; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020218:Response Elements / Q000235:genetics*; D012671:Seminiferous Tubules / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013076:Sperm Count; D013081:Sperm Motility; D013091:Spermatogenesis / Q000187:drug effects; D013739:Testosterone / Q000097:blood
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone