Human Nutrition Research Centre, Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK.
FASEB J. 2013 Aug;27(8):3323-34. doi: 10.1096/fj.12-224121. Epub 2013 Apr 19.
The mechanisms through which environmental and dietary factors modulate DNA repair are still unclear but may include dysregulation of gene expression due to altered epigenetic markings. In a mouse model, we investigated the effect of maternal folate depletion during pregnancy and lactation, and high-fat feeding from weaning, on base excision repair (BER) and DNA methylation and expression of selected BER-related genes in the brain of adult offspring. While folate depletion did not affect BER activity of the mothers, BER increased in the offspring at weaning (P=0.052). In the long term, as observed in 6-mo-old offspring, the double insult, i.e., maternal low-folate supply and high-fat feeding from weaning, decreased BER activity significantly in the cortex, cerebellum, hippocampus, and subcortical regions (P≤0.017). This fall in BER activity was associated with small changes in methylation or expression of BER-related genes. Maternal folate depletion led to slightly increased oxidative DNA damage levels in subcortical regions of adult offspring, which may increase sensitivity to oxidative stress and predispose to neurological disorders. In summary, our data suggest that low-folate supply during early life may leave an epigenetic mark that can predispose the offspring to further dietary insults, causing adverse effects during adult life.
环境和饮食因素调节 DNA 修复的机制尚不清楚，但可能包括由于表观遗传标记改变而导致的基因表达失调。在一个小鼠模型中，我们研究了母体在妊娠和哺乳期叶酸缺乏以及从断奶开始高脂肪喂养对成年后代大脑中碱基切除修复（BER）和 DNA 甲基化以及选定的 BER 相关基因表达的影响。虽然叶酸缺乏不影响母亲的 BER 活性，但在断奶时后代的 BER 增加（P=0.052）。从长期来看，正如在 6 个月大的后代中观察到的那样，即母体低叶酸供应和从断奶开始高脂肪喂养的双重打击，显著降低了皮质、小脑、海马和皮质下区域的 BER 活性（P≤0.017）。这种 BER 活性的下降与 BER 相关基因的甲基化或表达的微小变化有关。母体叶酸缺乏导致成年后代皮质下区域的氧化 DNA 损伤水平略有增加，这可能增加对氧化应激的敏感性，并使后代易患神经紊乱。总之，我们的数据表明，生命早期的低叶酸供应可能会留下表观遗传标记，使后代易受进一步的饮食挑战影响，从而在成年期产生不良影响。
