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

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. Graphical abstract Image 1 Highlights • Brca1 +/− knockout fetal brains exhibit enhanced NADPH oxidase (NOX) activity• In utero ethanol (EtOH) enhanced proteasomal activity & depleted fetal brain BRCA1• EtOH caused adaptive freezing behaviour in Brca1 +/+ progeny but not +/− littermates• PBN blocked the NOX increase, the EtOH decrease in BRCA1 and the freezing behaviour• BRCA1 protection includes NOX suppression; EtOH toxicity involves BRCA1 depletion

SUBMITTER: Drake D 

PROVIDER: S-EPMC8577473 | biostudies-literature |

REPOSITORIES: biostudies-literature