Genetically induced oxidative stress in mice causes thrombocytosis, splenomegaly and placental angiodysplasia that leads to recurrent abortion

Takamasa Ishii,Masaki Miyazawa,Yumi Takanashi,Maya Tanigawa,Kayo Yasuda,Hiromi Onouchi,Noboru Kawabe,Junji Mitsushita,Phil S Hartman,Naoaki Ishii

doi:10.1016/j.redox.2014.05.001

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 SDHCV69E 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.

Highlights

Introduction viability at20 weeks of gestation or when fetal weight is
Oxidative stress is well known to affect germ-cell development and testes in male infertility [21,22]. We addressed this using Tetmev-1, a mouse model characterized by chronic oxidative stress owing to the doxycycline-inducible expression of a defective complex II protein (SDHCV69E) involved in electron transport
We have demonstrated that a mitochondrial defect resulting from the SDHCV69E mutation causes mitochondrial and intracellular oxidative stress in the nematode C. elegans mev-1[15], a mev-1-mimic transgenic Drosophila model [33] and mouse embryonic fibroblast succinate dehydrogenase C subunit (SDHC) E69 cells [18]