Membrane-Localized Estrogen Receptor 1 Is Required for Normal Male Reproductive Development and Function in Mice

Endocrinology. 2016 Jul;157(7):2909-19. doi: 10.1210/en.2016-1085. Epub 2016 May 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Epididymis / metabolism
  • Estradiol / blood
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Follicle Stimulating Hormone / blood
  • Infertility, Male / genetics
  • Infertility, Male / metabolism*
  • Luteinizing Hormone / blood
  • Male
  • Mice
  • Mice, Knockout
  • Reproduction / physiology*
  • Sperm Motility / genetics*
  • Spermatogenesis / physiology*
  • Testosterone / blood

Substances

  • Estrogen Receptor alpha
  • Testosterone
  • Estradiol
  • Luteinizing Hormone
  • Follicle Stimulating Hormone