Novel mechanisms in alcohol neurodevelopmental disorders via BRCA1 depletion and BRCA1-dependent NADPH oxidase regulation

Danielle M Drake; Peter G Wells

doi:10.1016/j.redox.2021.102148

Novel mechanisms in alcohol neurodevelopmental disorders via BRCA1 depletion and BRCA1-dependent NADPH oxidase regulation

Redox Biol. 2021 Sep 23:48:102148. doi: 10.1016/j.redox.2021.102148. Online ahead of print.

Authors

Danielle M Drake¹, Peter G Wells²

Affiliations

¹ Department of Pharmaceutical Sciences and Centre for Pharmaceutical Oncology, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
² Department of Pharmaceutical Sciences and Centre for Pharmaceutical Oncology, Leslie Dan 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.

Abstract

The breast cancer 1 protein (BRCA1) facilitates DNA repair, preventing embryolethality and protecting the fetus from reactive oxygen species (ROS)-induced developmental disorders mediated by oxidatively damaged DNA. Alcohol (ethanol, EtOH) exposure during pregnancy causes fetal alcohol spectrum disorders (FASD), characterized by aberrant behaviour and enhanced ROS formation and proteasomal protein degradation. Herein, ROS-producing NADPH oxidase (NOX) activity was higher in Brca1 +/- vs. +/+ fetal and adult brains, and further enhanced by a single EtOH exposure. EtOH also enhanced catalase and proteasomal activities, while conversely reducing BRCA1 protein levels without affecting Brca1 gene expression. EtOH-initiated adaptive postnatal freezing behaviour was lost in Brca1 +/- progeny. Pretreatment with the free radical spin trap and ROS inhibitor phenylbutylnitrone blocked all EtOH effects, suggesting ROS-dependent mechanisms. This is the first in vivo evidence of NOX regulation by BRCA1, and of EtOH-induced, ROS-mediated depletion of BRCA1, revealing novel mechanisms of BRCA1 protection in FASD.

Keywords: Breast cancer 1 susceptibility gene (Brca1); Catalase; Fear conditioning; NADPH oxidase (NOX); Neurodevelopmental disorders; Proteasomal activity.