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

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