Parenteral nutrition (PN) is a means of administering intravenous nutrition to critically ill patients or individuals who cannot otherwise consume food through the normal oral route. Although PN is a critical part of patient care in many clinical situations, it must be carefully administered to avoid harmful side effects.
Infants may be especially vulnerable to complications caused by receiving suboptimal PN due to having specific nutrient requirements for growth and development. One other concern with PN mixtures is that they can undergo oxidation if exposed to light over time and become a source of harmful pro-oxidants which may leave infants vulnerable to health problems.
Researchers in Dr. Jean-Claude Lavoie’s lab at the University of Montreal were curious if early life PN would cause oxidative stress and subsequently alter the function of DNA methyltransferase (DNMT) enzymes which have a broadly important role in development by epigenetic programming.
In their study, they fed three-day old guinea pigs by the normal oral route or by PN containing either a high or low ratio of omega-3 to omega-6 fatty acids for four days. The rationale for using two types of PN solutions was because high omaga-3 solutions are even more vulnerable to oxidation. The researchers also determined if exposing PN solutions to light would cause oxidative stress in the liver. To measure DNMT activity in each group, the team used the EpiQuik DNMT Activity/Inhibition Assay Ultra Kit from EpiGentek.
Glutathione is a key antioxidant highly concentrated in the liver. All animals receiving PN showed an increase in the ratio of oxidized to reduced glutathione in the liver, indicating oxidative stress. Animals receiving the high omega-3 PN solution showed even more oxidative stress. Interestingly, only animals receiving PN solutions exposed to light showed reductions in hepatic vitamin C, which is another powerful antioxidant.
The oxidative stress caused by receiving PN was correlated with increased global DNA methylation which the authors determined by measuring 5-methylcytodine concentrations in the liver. Animals receiving PN showed higher DNA methyltransferase activity and higher concentrations the substrate for these reactions, S-adenosylmethionine which could explain higher DNA methylation.
Importantly, S-adenosylhomocysteine, which inhibits DNMT reactions was decreased in livers of animals receiving PN. Finally, concentrations of the DNMT1 protein were lower while concentrations of DNMT3a were higher in animals receiving PN. Importantly, DNMT3a has a major role in developmental programming of the epigenome while DNMT1 is responsible for maintaining DNA methylation during cell division.
According to the authors, this is the first time that a linear relationship between early life oxidative stress and altered DNA methylation has been determined using key metabolic biomarkers. Oxidative stress places increased demand for glutathione synthesis which would lower concentrations of the methyltransferase inhibitor S-adenosylhomocysteine and promote DNA methylation.
Although PN treatment caused oxidative stress and altered DNA methylation in liver, it is not understood whether these epigenetic marks are plastic and would eventually normalize once the animals went back to receiving oral nutrition.
Furthermore, future work must be done to observe whether these changes in DNA methylation are present on genes involving energy metabolism and whether they cause changes in gene expression. This would be an incredibly interesting future study as previous work by the same authors suggests PN causes lasting effects on energy metabolism in the same guinea pig model.
The results of this study show once again that early life exposures can alter the epigenome. PN has previously been reported to increase oxidative stress in infants requiring this type of nutrition. It is imperative that PN solutions continue to undergo innovation not only to deliver ideal nutrient quantities, but also prevent associated side effects including oxidative stress.
Mungala Lengo A. et al. (2020). Relationship between redox potential of glutathione and DNA methylation level in liver of newborn guinea pigs. Epigenetics.
Kleiber N. et al. (2010). Neonatal Exposure to Oxidants Induces Later in Life a Metabolic Response Associated to a Phenotype of Energy Deficiency in an Animal Model of Total Parenteral Nutrition. Pediatric Research.
Lavole JC. et al. (1997). Admixture of a multivitamin preparation to parenteral nutrition: the major contributor to in vitro generation of peroxides. Pediatrics.