Relationship between redox potential of glutathione and DNA methylation level in liver of newborn guinea pigs

Abstract

The metabolism of DNA methylation is reported to be sensitive to oxidant molecules or oxidative stress. Hypothesis: early-life oxidative stress characterized by the redox potential of glutathione influences the DNA methylation level. The in vivo study aimed at the impact of modulating redox potential of glutathione on DNA methylation. Newborn guinea pigs received different nutritive modalities for 4 days: oral nutrition, parenteral nutrition including lipid emulsion Intralipid (PN-IL) or SMOFLipid (PN-SF), protected or not from ambient light. Livers were collected for biochemical determinations. Redox potential (p < 0.001) and DNA methylation (p < 0.01) were higher in PN-infused animals and even higher in PN-SF. Their positive correlation was significant (r 2 = 0.51; p < 0.001). Methylation activity was higher in PN groups (p < 0.01). Protein levels of DNA methyltransferase (DNMT)-1 were lower in PN groups (p < 0.01) while those of both DNMT3a isoforms were increased (p < 0.01) and significantly correlated with redox potential (r 2 > 0.42; p < 0.001). The ratio of SAM (substrate) to SAH (inhibitor) was positively correlated with the redox potential (r 2 = 0.36; p < 0.001). In conclusion, early in life, the redox potential value strongly influences the DNA methylation metabolism, resulting in an increase of DNA methylation as a function of increased oxidative stress. These results support the notion that early-life oxidative stress can reprogram the metabolism epigenetically. This study emphasizes once again the importance of improving the quality of parenteral nutrition solutions administered early in life, especially to newborn infants. Abbreviation of Title: Parenteral nutrition and DNA methylation

Neonatal Vitamin C and Cysteine Deficiencies Program Adult Hepatic Glutathione and Specific Activities of Glucokinase, Phosphofructokinase, and Acetyl-CoA Carboxylase in Guinea Pigs’ Livers

“…The relationship between the redox potential of glutathione and DNA methylation in the liver of one-week-old guinea pigs has been previously reported. Oxidation of redox potential strongly correlated with increased methylation [59,60], while the methylation of the glucokinase gene promoter was increased with age and associated with the risk of metabolic disease [61,62]. If this relationship could explain our observation, it also suggests that methylation of DNA during neonatal period may not be permanent.…”

Glutathione Supplementation Prevents Neonatal Parenteral Nutrition-Induced Short- and Long-Term Epigenetic and Transcriptional Disruptions of Hepatic H2O2 Metabolism in Guinea Pigs

“…Experimental procedures have been described in previous studies [ 15 , 17 ]. Forty-two male Hartley guinea pigs were purchased from Charles River Laboratories (St-Constant, QC, Canada) on their third day of life.…”

“…They were housed in the institutional animal facility at constant temperature and humidity as well as 12 h light–12 h dark cycle. Upon arrival, one third received standard guinea pig oral nutrition (ON, control group) and two thirds were fed exclusively by parenteral nutrition (PN group) via a catheter inserted in the jugular vein as previously described [ 15 , 17 ]. Half of animals from PN group received PN solution enriched with disulfide glutathione (PN+GSSG group).…”

“…In newborn guinea pigs, an infusion of various intravenous solutions containing different levels of oxidizing molecules, such as peroxides, induced a disturbance in the glutathione levels characterized by an oxidation of the redox potential. This oxidation was strongly correlated with the activation of DNA methyltransferase (DNMT) 3a1-2 and overall DNA hypermethylation [ 17 ]. Therefore, it was hypothesized that early peroxide exposure could induce a permanent change in the regulation of glucose and lipid metabolism through an epigenetic modification of specific genes.…”

Narrative Review of n-3 Polyunsaturated Fatty Acid Supplementation upon Immune Functions, Resolution Molecules and Lipid Peroxidation

“…The fish oil containing lipid emulsion increased oxidative stress and apoptosis and impaired alveolar development compared with the soybean lipid emulsion. Lengo et al [ 106 ] evaluated oxidation and DNA methylation in the livers of newborn guinea pigs. Animals received an enteral diet or parenteral nutrition with soybean intravenous lipid emulsion or fish oil containing intravenous lipid emulsion (SMOFlipid, Fresenius Kabi, Bad Homburg, Germany; containing soybean oil, medium chain triglycerides, olive oil, fish oil).…”