Maternal folate depletion and high‐fat feeding from weaning affects DNA methylation and DNA repair in brain of adult offspring

Abstract

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.

Comet assay to measure DNA repair: approach and applications

“…Although comet-based assays are easy to use, sensitive, versatile, and relatively inexpensive, to the best of our knowledge, there are only a few reports that describe the use of animal tissue extracts in the comet-based assay to measure activities of NER (Langie et al, 2010a) or BER (Mikkelsen et al, 2009; Langie et al, 2011, 2013, 2014; Gorniak et al, 2013) in vitro .…”

The Influence of Early Life Nutrition on Epigenetic Regulatory Mechanisms of the Immune System

“…Another study investigated the effect of folate deficiency during pregnancy and lactation and of high-fat feeding from weaning on DNA methylation and the expression of selected genes in adult offspring brain in a mouse model. The results suggest that low folate supply during early life may cause an epigenetic effect in offspring, leading to an increased sensibility to further dietary insults [30]. …”

Role of early life exposure and environment on neurodegeneration: implications on brain disorders

“…Performance in Morris maze experiments is affected in pups born to mice fed on high fat diet during gestational and lactation period and the results were attributed to decreased cell proliferation [34]. Similarly, studies have shown that maternal folate depletion results in oxidative stress and epigenetic changes in the offspring [35] which ultimately lead to neurodegeneration. Further elevated levels of homocysteine in mother were shown to increase oxidative stress in pups brain leading to apoptosis, as marked by DNA fragmentation [36].…”