Impact of endoplasmic reticulum stress on oocyte aging mechanisms

Mol Hum Reprod. 2020 Aug 1;26(8):567-575. doi: 10.1093/molehr/gaaa040.

Abstract

Endoplasmic reticulum (ER) stress is associated with several aging-related diseases; however, the mechanism underlying age-related deterioration of oocyte quality is unclear. Here, we used post-ovulatory, in vivo aged mouse oocytes as a model. Super-ovulated oocytes harvested from the oviduct at 14 h and 20 h post-hCG injection were designated as 'fresh' and 'aged', respectively. Embryo development following IVF was compared between fresh, aged and ER stress-induced oocytes. Expression of the ER stress marker GRP78 was examined at each stage. To evaluate the effect of salubrinal, an ER stress suppressor, on embryo development following IVF, expression levels of GRP78 and phospho-eukaryotic initiation factor 2 alpha were compared between aged and salubrinal-treated aged oocytes. Embryo transfer of salubrinal-treated aged oocytes was performed to examine the safety of salubrinal. Similar to aged oocytes, ER stress-induced oocytes showed lower fertilization rates and poor embryo development. Following IVF, expression of GRP78 decreased with embryo development. GRP78 expression was significantly higher in aged oocytes than in fresh oocytes. Salubrinal lowered GRP78 levels and improved embryo development. No adverse effect of salubrinal treatment was found on the birth weight of pups or on organogenesis in mice. The limitation of this study was that protein kinase-like ER kinase was the only ER stress pathway examined; the role of IRE1 and ATF6 pathways was not considered. Nevertheless, salubrinal can significantly improve embryo development in in vivo aged oocytes undergoing ER stress. Hence, regulation of ER stress might represent a promising therapeutic strategy to overcome poor oocyte quality.

Keywords: ER stress; GRP78; PERK; eIF2α; endoplasmic reticulum; mouse oocyte; oocyte aging; salubrinal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cinnamates / metabolism
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress / genetics
  • Endoplasmic Reticulum Stress / physiology*
  • Female
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Male
  • Mice
  • Oocytes / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Thiourea / analogs & derivatives
  • Thiourea / metabolism
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism

Substances

  • Cinnamates
  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins
  • Hspa5 protein, mouse
  • salubrinal
  • PERK kinase
  • Protein Serine-Threonine Kinases
  • eIF-2 Kinase
  • eIF2alpha kinase, mouse
  • Thiourea