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      Breast cancer 1 (BRCA1) protection in altered gene expression and neurodevelopmental disorders due to physiological and ethanol-enhanced reactive oxygen species formation.

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          Abstract

          The breast cancer 1 (Brca1) susceptibility gene regulates the repair of reactive oxygen species (ROS)-mediated DNA damage, which is implicated in neurodevelopmental disorders. Alcohol (ethanol, EtOH) exposure during pregnancy causes fetal alcohol spectrum disorders (FASD), including abnormal brain function, associated with enhanced ROS-initiated DNA damage. Herein, oxidative DNA damage in fetal brains and neurodevelopmental disorders were enhanced in saline-exposed +/- vs. +/+ Brca1 littermates. A single EtOH exposure during gestation further enhanced oxidative DNA damage, altered the expression of developmental/DNA damage response genes in fetal brains, and resulted in neurodevelopmental disorders, all of which were BRCA1-dependent. Pretreatment with the ROS inhibitor phenylbutylnitrone (PBN) blocked DNA damage and some neurodevelopmental disorders in both saline- and EtOH-exposed progeny, corroborating a ROS-dependent mechanism. Fetal BRCA1 protects against altered gene expression and neurodevelopmental disorders caused by both physiological and EtOH-enhanced levels of ROS formation. BRCA1 deficiencies may enhance the risk for FASD.

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          Author and article information

          Journal
          Free Radic Biol Med
          Free radical biology & medicine
          Elsevier BV
          1873-4596
          0891-5849
          Nov 01 2023
          : 208
          Affiliations
          [1 ] Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Centre for Pharmaceutical Oncology, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
          [2 ] Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
          [3 ] Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
          [4 ] Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
          [5 ] Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Centre for Pharmaceutical Oncology, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: pg.wells@utoronto.ca.
          Article
          S0891-5849(23)00578-6
          10.1016/j.freeradbiomed.2023.08.006
          37541454
          d9e8879d-a471-4313-a5a6-7c3c152ddb74
          History

          Neurodevelopmental disorders,Reactive oxygen species (ROS),Repetitive behaviours,Alcohol (ethanol),Behavioural disorders,Breast cancer 1 susceptibility gene (Brca1),DNA damage,Executive function,Fetal alcohol spectrum disorders (FASD),Gene expression,Learning and memory,Motor coordination

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