title: Maternal insulin resistance causes oxidative stress and mitochondrial dysfunction in mouse oocytes.
abstract: BACKGROUND
  Insulin resistance (IR) and hyperinsulinemia compromise fertility in females and are well-recognized characteristics of anovulatory women with polycystic ovary syndrome. Patients with IR and hyperinsulinemia undergoing ovarian stimulation for IVF are at increased risks of impaired oocyte developmental competence, implantation failure and pregnancy loss. However, the precise underlying mechanism remains unknown.
  
  
  METHODS
  We investigated how IR impairs oocyte quality and early embryonic development by an insulin-resistant mouse model. Oocyte quality, fertilization and embryonic development were analyzed. Furthermore, oxidant stress products and mitochondrial function were evaluated by quantitative real-time PCR and immunofluorescence.
  
  
  RESULTS
  An imbalance between oxidants and antioxidants revealed by increased concentrations of reactive oxygen species, and a decreased concentration of glutathione (GSH) and a decreased GSH/GSSG ratio resulted in oxidative stress (OS) and impaired mitochondrial function in germinal vesicle (GV) and metaphase II (MII) oocytes of insulin-resistant mice. MII oocytes displayed a decrease in the ATP content and the mitochondrial DNA (mtDNA) copy number. In contrast, GV oocytes were characterized by a high ATP content concomitant with increased clustering of mitochondria and a high inner mitochondrial membrane potential. GV oocytes from insulin-resistant mice showed early stage apoptosis, and fewer MII oocytes could be retrieved from these mice and were of poor quality associated with decreased fertilization and an arrest of embryo development with increased fragmentation. Abnormal spindles and misaligned chromosomes of MII oocyte were significantly increased in IR and hyperinsulinemia mice compared with the control mice.
  
  
  CONCLUSIONS
  IR contributes to OS and disrupts mitochondrial function in mouse oocytes. This may impair the accurate transmission of mtDNA from one generation to the next. Therefore, our results suggest that OS and mitochondrial dysfunction are responsible for poor oocyte quality of insulin-resistant mice, and may provide novel targets to improve low fertility in females with IR.
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, #1 Beichen West Road, Beijing 100101, People's Republic of China.
authors.forename: Xiang-Hong
authors.initials: XH
authors.lastname: Ou
authors.forename: Sen
authors.initials: S
authors.lastname: Li
authors.forename: Zhen-Bo
authors.initials: ZB
authors.lastname: Wang
authors.forename: Mo
authors.initials: M
authors.lastname: Li
authors.forename: Song
authors.initials: S
authors.lastname: Quan
authors.forename: Fuqi
authors.initials: F
authors.lastname: Xing
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Shi-Bin
authors.initials: SB
authors.lastname: Chao
authors.forename: Zijiang
authors.initials: Z
authors.lastname: Chen
authors.forename: Xing-Wei
authors.initials: XW
authors.lastname: Liang
authors.forename: Yi
authors.initials: Y
authors.lastname: Hou
authors.forename: Heide
authors.initials: H
authors.lastname: Schatten
authors.forename: Qing-Yuan
authors.initials: QY
authors.lastname: Sun
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D006063:Chorionic Gonadotropin / Q000627:therapeutic use; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005307:Fertilization in Vitro; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000627:therapeutic use; D007333:Insulin Resistance; D008677:Metaphase; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000378:metabolism; D009865:Oocytes / Q000166:cytology*; D016877:Oxidants / Q000737:chemistry; D018384:Oxidative Stress; D011085:Polycystic Ovary Syndrome / Q000378:metabolism; D017382:Reactive Oxygen Species
chemical_list: D000975:Antioxidants; D006063:Chorionic Gonadotropin; D004272:DNA, Mitochondrial; D007328:Insulin; D016877:Oxidants; D017382:Reactive Oxygen Species; D005978:Glutathione