Data from: Hyperandrogenism and insulin resistance induce gravid uterine defects in association with mitochondrial dysfunction and aberrant ROS production

Women with polycystic ovary syndrome (PCOS) are at increased risk of
miscarriage, which often accompanies the hyperandrogenism and insulin
resistance seen in these patients. However, neither the combinatorial
interaction between these two PCOS-related etiological factors nor the
mechanisms of their actions in the uterus during pregnancy are well
understood. We hypothesised that hyperandrogensim and insulin resistance
exert a causative role in miscarriage by inducing defects in uterine
function that are accompanied by mitochondrial-mediated oxidative stress,
inflammation and perturbed gene expression. Here we tested this hypothesis
by studying the metabolic, endocrine and uterine abnormalities in pregnant
rats after exposure to daily injection of 5α-dihydrotestosterone (DHT,
1.66 mg/kg body weight/day) and/or insulin (6.0 IU/day) from gestational
day 7.5 to 13.5. We showed that while DHT-exposed and insulin-exposed
pregnant rats presented impaired insulin sensitivity, DHT+insulin-exposed
pregnant rats exhibited hyperandrogenism and peripheral insulin
resistance, which mirrors pregnant PCOS patients. Compared to controls,
hyperandrogenism and insulin resistance in the dam was associated with
alterations in uterine morphology and aberrant expression of genes
responsible for decidualization (Prl8a2, Fxyd2, and Mt1g), placentation
(Fcgr3 and Tpbpa), angiogenesis (Flt1, Angpt1, Angpt2, Ho1, Ccl2, Ccl5,
Cxcl9, and Cxcl10) and insulin signaling (Akt, Gsk3 and Gluts). Moreover,
we observed changes in uterine mitochondrial function and homeostasis
(i.e. mitochondrial DNA copy number and the expression of genes
responsible for mitochondrial fusion, fission, biogenesis, and mitophagy)
and suppression of both oxidative and antioxidative defenses (i.e.
reactive oxygen species, Nrf2 signaling, and interactive networks of
antioxidative stress responses) in response to the hyperandrogenism and
insulin resistance. These findings demonstrate that hyperandrogenism and
insulin resistance induce mitochondria-mediated damage and a resulting
imbalance between oxidative and antioxidative stress responses in the
gravid uterus.