Gestational Arsenic Trioxide Exposure Acts as a Developing Neuroendocrine-Disruptor by Downregulating Nrf2/PPARγ and Upregulating Caspase-3/NF-ĸB/Cox2/BAX/iNOS/ROS.

The goal of this investigation was to evaluate the effects of gestational administrations of arsenic trioxide (ATO; AsO) on fetal neuroendocrine development (the thyroid-cerebrum axis). Pregnant Wistar rats were orally administered ATO (5 or 10 mg/kg) from gestation day (GD) 1 to 20. Both doses of ATO diminished free thyroxine and free triiodothyronine levels and augmented thyrotropin level in both dams and fetuses at GD 20. Also, the maternofetal hypothyroidism in both groups caused a dose-dependent reduction in the fetal serum growth hormone, insulin growth factor-I (IGF-I), and IGF-II levels at embryonic day (ED) 20. These disorders perturbed the maternofetal body weight, fetal brain weight, and survival of pregnant and their fetuses. In addition, destructive degeneration, vacuolation, hyperplasia, and edema were observed in the fetal thyroid and cerebrum of both ATO groups at ED 20. These disruptions appear to depend on intensification in the values of lipid peroxidation, nitric oxide, and HO, suppression of messenger RNA (mRNA) expression of nuclear factor erythroid 2-related factor 2 and peroxisome proliferator-activated receptor gamma, and activation of mRNA expression of caspase-3, nuclear factor kappa-light-chain-enhancer of activated B cells, cyclooxygenase-2, Bcl-2-associated X protein, and inducible nitric oxide synthase in the fetal cerebrum. These data suggest that gestational ATO may disturb thyroid-cerebrum axis generating fetal neurodevelopmental toxicity.