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 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.

Oxidative Stress: Placenta Function and Dysfunction

“…81 Additionally, Tet-mev-1 conditional transgenic mice, which have a dysfunctional mitochondrial respiratory chain, can mimic OS-related miscarriage. 82 Thus, both CBA/J 9 DBA/2 and Tet-mev-1 mice can link placental OS with pregnancy losses and provide powerful animal models for the evaluation of better treatment approaches. 81,82 Immune microenvironment and spontaneous abortion uNK cells may be biologically necessary to maintain successful pregnancy.…”

“…82 Thus, both CBA/J 9 DBA/2 and Tet-mev-1 mice can link placental OS with pregnancy losses and provide powerful animal models for the evaluation of better treatment approaches. 81,82 Immune microenvironment and spontaneous abortion uNK cells may be biologically necessary to maintain successful pregnancy. [83][84][85] However, Clifford et al 86 showed increased CD56 + NK cells in the endometrium of recurrent early abortion, which suggests a possible role for NK cells in this disease.…”

Genetic Factors Associated With Recurrent Pregnancy Loss

“…This further lead to the inflammation of the placenta and abnormal angiogenesis and resulted in spontaneous abortion. Thus oxidative stress influences the occurrence of RPL [22].…”

Endogenous reactive oxygen species cause astrocyte defects and neuronal dysfunctions in the hippocampus: a new model for aging brain

“…Tet‐mev‐1 conditional transgenic mice grew to normal size in 12 weeks after suffering of low birthweight and initial growth retardation. They had low fertility and recurrent miscarriages (Ishii et al ., , ). After normal development, male and female Tet‐mev‐1 mice showed accelerated corneal dysfunctions with age, that is , delayed epithelialization with keratitis, decreasing endothelial cells such as Fuch's corneal dystrophy, and thickened Descemet's membrane (Onouchi et al ., ).…”