Drake Danielle M, Wells Peter G
Department of Pharmaceutical Sciences and Centre for Pharmaceutical Oncology, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
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.
Redox Biol. 2021 Sep 23;48:102148. doi: 10.1016/j.redox.2021.102148.
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，防止胚胎致死，并保护胎儿免受由氧化损伤DNA介导的活性氧（ROS）诱导的发育障碍。孕期酒精（乙醇，EtOH）暴露会导致胎儿酒精谱系障碍（FASD），其特征为行为异常、ROS生成增加以及蛋白酶体蛋白降解增强。在此，与野生型（+/+）胎儿和成年大脑相比，Brca1杂合子（+/-）大脑中产生ROS的烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）活性更高，且单次EtOH暴露会使其进一步增强。EtOH还增强了过氧化氢酶和蛋白酶体活性，而相反地降低了BRCA1蛋白水平，却不影响Brca1基因表达。EtOH引发的适应性产后僵住行为在Brca1杂合子（+/-）后代中消失。用自由基自旋捕获剂和ROS抑制剂苯基丁基硝酮预处理可阻断所有EtOH效应，提示存在ROS依赖性机制。这是BRCA1对NOX调节以及EtOH诱导的、ROS介导的BRCA1耗竭的首个体内证据，揭示了BRCA1在FASD中保护作用的新机制。
