Developmental role of nuclear factor E2-related factor 2 in mitigating methamphetamine fetal toxicity and postnatal neurodevelopmental deficits

Abstract

Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that mediates protective responses to oxidative stress, but its developmental role is unknown. Herein, we treated pregnant Nrf2-deficient knockout mice with methamphetamine (METH) (5–40mg/kg ip), which increases fetal reactive oxygen species (ROS) and oxidatively damaged DNA in fetal brain tissue. METH-exposed Nrf2−/− fetuses were unable to increase mRNA levels of ROS-protective heme oxygenase-1, NAD(P)H:quinone oxidoreductase, or oxoguanine glycosylase 1, unlike wild-type controls, and exhibited enhanced DNA oxidation, fetal resorption, edema, and reduced fetal weight, with greater toxicity in female Nrf2−/− fetuses. Postnatal neurodevelopmental deficits in activity and olfactory function were exacerbated, with gender-dependent differences, and the olfactory bulb GABAergic marker GAD-65 was decreased in Nrf2−/− offspring exposed in utero to METH. In utero METH-initiated olfactory deficits may be a sensitive postnatal functional test for long-term neurotoxicity, and indicated a broad fetal role for Nrf2. The results show that fetal Nrf2 deficiency enhances METH-initiated oxidative DNA damage and toxicity, suggesting that Nrf2 activation of cytoprotective proteins mitigates the effects of ROS and their oxidative damage to cellular macromolecules, thereby protecting the developing fetus from adverse structural and postnatal neurodevelopmental consequences.