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.

乳腺癌 1 蛋白 ( BRCA1 ) 促进 DNA 修复，防止胚胎死亡并保护胎儿免受氧化损伤 DNA 介导的活性氧 ( ROS ) 诱导的发育障碍。怀孕期间接触酒精（乙醇，EtOH）会导致胎儿酒精谱系障碍（FASD），其特征是异常行为和增强的 ROS 形成和蛋白酶体蛋白降解。在此，Brca1  +/− 与 +/+ 胎儿和成人大脑中产生 ROS 的 NADPH 氧化酶 ( NOX ) 活性更高，并且通过单次 EtOH 暴露进一步增强。EtOH 还增强了过氧化氢酶和蛋白酶体的活性，同时相反地降低了 BRCA1 蛋白水平而不影响Brca1基因表达。EtOH 引发的适应性出生后冷冻行为在Brca1  +/- 后代中丢失。用自由基自旋阱和 ROS 抑制剂苯基丁基硝酮预处理可阻断所有 EtOH 效应，表明存在 ROS 依赖性机制。这是BRCA1 调节 NOX 和乙醇诱导的、ROS 介导的 BRCA1 耗竭的第一个体内证据，揭示了 FASD 中 BRCA1 保护的新机制。