Developmental role of nuclear factor E2-related factor 2 in mitigating methamphetamine fetal toxicity and postnatal neurodevelopmental deficits |
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| Affiliation: | 1. Department of Immunology and Pathogenic Biology, Xi''an Jiaotong University School of Basic Medical Sciences, Xi''an 710061, China;2. Department of Laboratory, The Second Affiliated Hospital of Medical College of Xi''an Jiaotong University, Xi''an 71004, China;3. Department of Cardiovascular Surgery, The First Affiliated Hospital of Medical College of Xi''an Jiaotong University, Xi''an 710061, China;4. Pathology Department, The Second Affiliated Hospital of Medical College of Xi''an Jiaotong University, Xi''an 710004, China;5. VIP Internal Medicine Department, Lanzhou University Second Hospital, Lanzhou 730030, China;6. Graduate Teaching and Experiment Centre, Xi''an Jiaotong University School of Basic Medical Sciences, Xi''an 710061, China;7. Forensic Medicine College of Xi''an Jiaotong University, Key Laboratory of the Health Ministry for Forensic Medicine, Key Laboratory of the Ministry of Education for Environment and Genes Related to Diseases, Xi''an 710061, China;1. Missouri State University, Department of Psychology, 901 S. National Avenue, Springfield, MO 65897, USA;2. Brown Center for the Study of Children at Risk, Department of Pediatrics, Women & Infants Hospital, 101 Dudley Street, Providence, RI 02905, USA;3. Department of Pediatrics, Warren Alpert Medical School of Brown University, Providence, RI, USA;4. Department of Psychiatry & Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI, USA;5. Department of Pediatrics, Wayne State University School of Medicine, 3901 Beaubien Blvd., Detroit, MI 48201, USA;6. Department of Pediatrics, University of Kentucky Hospital, 800 Rose St., Rm MS-473, Lexington, KY 40536, USA;7. Department of Pediatrics, University of Miami, Miller School of Medicine, P.O. Box 016960 (R-131), Miami, FL 33136, USA |
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| 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) (5–40 mg/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. |
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| Keywords: | Nuclear factor E2-related factor 2 Nrf2 Methamphetamine DNA oxidation Fetal toxicity Neurodevelopmental deficits Free radicals |
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