Total parenteral nutrition induces sustained hypomethylation of DNA in newborn guinea pigs

Abstract

Neonatal total parenteral nutrition (TPN) is associated with animals with low glucose tolerance, body weight, and physical activity at adulthood. The early life origin of adult metabolic perturbations suggests a reprogramming of metabolism following epigenetic modifications induced by a change in the pattern of DNA expression. We hypothesized that peroxides contaminating TPN inhibit the activity of DNA methyltransferase (DNMT), leading to a modified DNA methylation state. Three groups of 3-d-old guinea pigs with catheters in their jugular veins were compared: (i) control: enterally fed with regular chow; (ii) TPN: fed exclusively with TPN (dextrose, amino acids, lipids, multivitamins, contaminated with 350 ± 29 μmol/l peroxides); (iii) H2O2: control + 350 μmol/l H2O2 intravenously. After 4 d, infusions were stopped and animals enterally fed. Half the animals were killed immediately after treatments and half were killed 8 wk later (n = 4-6 per group) for hepatic determination of DNMT activities and of 5'-methyl-2'-deoxycytidine (5MedCyd) levels, a marker of DNA methylation. At 1 wk, DNMT and 5MedCyd were lower in the TPN and H2O2 groups as compared with controls. At 9 wk, DNMT remained lower in the TPN group, whereas 5MedCyd was lower in the TPN and H2O2 groups. Administration of TPN or H2O2 early in life in guinea pigs induces a sustained hypomethylation of DNA following inhibition of DNMT activity.