Department of Neuroscience and Physiology, State University of New York - Upstate Medical University, Syracuse, NY 13210, USA; Developmental Exposure Alcohol Research Center, Binghamton NY 13902, Cortland NY 13045, and Syracuse, NY 13210, USA.
Department of Neuroscience and Physiology, State University of New York - Upstate Medical University, Syracuse, NY 13210, USA; Developmental Exposure Alcohol Research Center, Binghamton NY 13902, Cortland NY 13045, and Syracuse, NY 13210, USA; Department of Anatomy, Touro College of Osteopathic Medicine, Middletown, NY 10940, USA; Research Service, Veterans Affairs Medical Center, Syracuse, NY 13210, USA.
Exp Neurol. 2019 Jul;317:214-225. doi: 10.1016/j.expneurol.2019.02.003. Epub 2019 Mar 8.
Following neurotoxic damage, cells repair their DNA, and survive or undergo apoptosis. This study tests the hypothesis that ethanol induces a DNA damage response (DDR) in neural stem cells (NSCs) that promotes excision repair (ER) and this repair is influenced by the growth factor environment. Non-immortalized NSCs treated with fibroblast growth factor 2 or transforming growth factor (TGF) β1 were exposed to ethanol. Ethanol increased total DNA damage, reactive oxygen species, and oxidized DNA bases. TGFβ1 potentiated these toxic effects. Transcriptional analyses of cultured NSCs revealed ethanol-induced increases in transcripts related to the DDR (e.g., Hus1 and p53), base ER (e.g., Mutyh and Nthl1), and nucleotide ER (e.g., Xpc), particularly in the presence of TGFβ1. Expression and activity of ER proteins were affected by ethanol. Similar changes occurred in proliferating cells of ethanol-treated mouse fetuses. Ethanol-induced DNA repair in NSCs depends on the ambient growth factors. Gene products for DNA repair in stem cells are among the first biomarkers identifying fetal alcohol-induced damage.
神经毒性损伤后，细胞会修复其 DNA 并存活或发生细胞凋亡。本研究检验了以下假设：乙醇在神经干细胞（NSC）中诱导 DNA 损伤反应（DDR），促进切除修复（ER），并且这种修复受生长因子环境的影响。用成纤维细胞生长因子 2 或转化生长因子（TGF）β1 处理的非永生化 NSC 暴露于乙醇中。乙醇增加了总 DNA 损伤、活性氧和氧化的 DNA 碱基。TGFβ1 增强了这些毒性作用。对培养的 NSC 的转录分析显示，乙醇诱导与 DDR（例如 Hus1 和 p53）、碱基 ER（例如 Mutyh 和 Nthl1）和核苷酸 ER（例如 Xpc）相关的转录本增加，尤其是在存在 TGFβ1 的情况下。ER 蛋白的表达和活性受到乙醇的影响。在乙醇处理的胎鼠增殖细胞中也发生了类似的变化。NSC 中乙醇诱导的 DNA 修复取决于环境生长因子。干细胞中用于 DNA 修复的基因产物是最早识别胎儿酒精诱导损伤的生物标志物之一。
