title: Genetically induced oxidative stress in mice causes thrombocytosis, splenomegaly and placental angiodysplasia that leads to recurrent abortion.
abstract: Historical data in the 1950s suggests that 7%, 11%, 33%, and 87% of couples were infertile by ages 30, 35, 40 and 45, respectively. Up to 22.3% of infertile couples have unexplained infertility. Oxidative stress is associated with male and female infertility. However, there is insufficient evidence relating to the influence of oxidative stress on the maintenance of a viable pregnancy, including pregnancy complications and fetal development. Recently, we have established Tet-mev-1 conditional transgenic mice, which can express the doxycycline-induced mutant SDHC(V69E) transgene and experience mitochondrial respiratory chain dysfunction leading to intracellular oxidative stress. In this report, we demonstrate that this kind of abnormal mitochondrial respiratory chain-induced chronic oxidative stress affects fertility, pregnancy and delivery rates as well as causes recurrent abortions, occasionally resulting in maternal death. Despite this, spermatogenesis and early embryogenesis are completely normal, indicating the mutation's effects to be rather subtle. Female Tet-mev-1 mice exhibit thrombocytosis and splenomegaly in both non-pregnant and pregnant mice as well as placental angiodysplasia with reduced Flt-1 protein leading to hypoxic conditions, which could contribute to placental inflammation and fetal abnormal angiogenesis. Collectively these data strongly suggest that chronic oxidative stress caused by mitochondrial mutations provokes spontaneous abortions and recurrent miscarriage resulting in age-related female infertility.
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyazawa
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Takanashi
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Tanigawa
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan ; Education and Research Support Center, Tokai University, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Department of Ophthalmology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Onouchi
authors.affiliation: Education and Research Support Center, Tokai University, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Kawabe
authors.affiliation: Department of Obstetrics and Gynecology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya, Saitama 330-8503, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Mitsushita
authors.affiliation: Department of Biology, Texas Christian University, Fort Worth, TX 76129, USA.
authors.forename: Phil S
authors.initials: PS
authors.lastname: Hartman
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Ishii
mesh_terms: D000026:Abortion, Habitual; D019943:Amino Acid Substitution; D016888:Angiodysplasia / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D050050:Protein Carbonylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013091:Spermatogenesis; D013163:Splenomegaly; D013922:Thrombocytosis / Q000378:metabolism / Q000473:pathology*
chemical_list: D008565:Membrane Proteins; D017382:Reactive Oxygen Species; C582347:SDHC protein, mouse
keywords: Abortion; Infertility; Mitochondria; NGF, non-growing follicles; Oxidative stress; PLGF, placenta growth factor; ROS, reactive oxygen species; SDH, succinate dehydrogenase; SDHC; SDHC, succinate dehydrogenase C subunit; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; VEGF, vascular endothelial growth factors; VEGFR-1, VEGF receptor-1