title: Membrane-Localized Estrogen Receptor 1 Is Required for Normal Male Reproductive Development and Function in Mice.
abstract: Estrogen receptor 1 (ESR1) mediates major reproductive functions of 17β-estradiol (E2). Male Esr1 knockout (Esr1KO) mice are infertile due to efferent ductule and epididymal abnormalities. The majority of ESR1 is nuclear/cytoplasmic; however, a small fraction is palmitoylated at cysteine 451 in mice and localized to cell membranes, in which it mediates rapid E2 actions. This study used an Esr1 knock-in mouse containing an altered palmitoylation site (C451A) in ESR1 that prevented cell membrane localization, although nuclear ESR1 was expressed. These nuclear-only estrogen receptor 1 (NOER) mice were used to determine the roles of membrane ESR1 in males. Epididymal sperm motility was reduced 85% in 8-month-old NOER mice compared with wild-type controls. The NOER mice had decreased epididymal sperm viability and greater than 95% of sperm had abnormalities, including coiled midpieces and tails, absent heads, and folded tails; this was comparable to 4-month Esr1KO males. At 8 months, daily sperm production in NOER males was reduced 62% compared with controls. The NOER mice had histological changes in the rete testes, efferent ductules, and seminiferous tubules that were comparable with those previously observed in Esr1KO males. Serum T was increased in NOER males, but FSH, LH, and E2 were unchanged. Critically, NOER males were initially subfertile, becoming infertile with advancing age. These findings identify a previously unknown role for membrane ESR1 in the development of normal sperm and providing an adequate environment for spermatogenesis.
authors.affiliation: Department of Physiological Sciences (M.K.N., T.I.M., S.H.L., P.S.C.), University of Florida, Gainesville, Florida 32610; Department of Comparative Biosciences (R.A.H.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Division of Endocrinology (E.R.L.), Department of Medicine, University of California, Irvine, Irvine, California 92697; and Department of Veterans Affairs Medical Center (E.R.L.), Long Beach, Long Beach, California 90822.
authors.forename: Manjunatha K
authors.initials: MK
authors.lastname: Nanjappa
authors.affiliation: Department of Physiological Sciences (M.K.N., T.I.M., S.H.L., P.S.C.), University of Florida, Gainesville, Florida 32610; Department of Comparative Biosciences (R.A.H.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Division of Endocrinology (E.R.L.), Department of Medicine, University of California, Irvine, Irvine, California 92697; and Department of Veterans Affairs Medical Center (E.R.L.), Long Beach, Long Beach, California 90822.
authors.forename: Rex A
authors.initials: RA
authors.lastname: Hess
authors.affiliation: Department of Physiological Sciences (M.K.N., T.I.M., S.H.L., P.S.C.), University of Florida, Gainesville, Florida 32610; Department of Comparative Biosciences (R.A.H.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Division of Endocrinology (E.R.L.), Department of Medicine, University of California, Irvine, Irvine, California 92697; and Department of Veterans Affairs Medical Center (E.R.L.), Long Beach, Long Beach, California 90822.
authors.forename: Theresa I
authors.initials: TI
authors.lastname: Medrano
authors.affiliation: Department of Physiological Sciences (M.K.N., T.I.M., S.H.L., P.S.C.), University of Florida, Gainesville, Florida 32610; Department of Comparative Biosciences (R.A.H.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Division of Endocrinology (E.R.L.), Department of Medicine, University of California, Irvine, Irvine, California 92697; and Department of Veterans Affairs Medical Center (E.R.L.), Long Beach, Long Beach, California 90822.
authors.forename: Seth H
authors.initials: SH
authors.lastname: Locker
authors.affiliation: Department of Physiological Sciences (M.K.N., T.I.M., S.H.L., P.S.C.), University of Florida, Gainesville, Florida 32610; Department of Comparative Biosciences (R.A.H.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Division of Endocrinology (E.R.L.), Department of Medicine, University of California, Irvine, Irvine, California 92697; and Department of Veterans Affairs Medical Center (E.R.L.), Long Beach, Long Beach, California 90822.
authors.forename: Ellis R
authors.initials: ER
authors.lastname: Levin
authors.affiliation: Department of Physiological Sciences (M.K.N., T.I.M., S.H.L., P.S.C.), University of Florida, Gainesville, Florida 32610; Department of Comparative Biosciences (R.A.H.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Division of Endocrinology (E.R.L.), Department of Medicine, University of California, Irvine, Irvine, California 92697; and Department of Veterans Affairs Medical Center (E.R.L.), Long Beach, Long Beach, California 90822.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Cooke
mesh_terms: D000818:Animals; D004822:Epididymis / Q000378:metabolism; D004958:Estradiol / Q000097:blood; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005640:Follicle Stimulating Hormone / Q000097:blood; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012098:Reproduction / Q000502:physiology*; D013081:Sperm Motility / Q000235:genetics*; D013091:Spermatogenesis / Q000502:physiology*; D013739:Testosterone / Q000097:blood
chemical_list: D047628:Estrogen Receptor alpha; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone