Methyl group metabolism in maternal and fetal hepatic tissues is altered by diabetes and retinoic acid treatment

Abstract

Adequate methyl group supply is vital for numerous biological reactions, especially during development. A lack of methyl groups, B‐vitamins, and changes in relevant enzymes, can result in a host of pathologies, including neural tube defects. If inappropriately activated, hepatic glycine N‐methyltransferase (GNMT) a regulatory enzyme in folate and methyl group metabolism, leads to methyl deficiency. We have shown that both a diabetic state and retinoic acid (RA) treatment result in activation of GNMT. The goal of this pilot study was to determine if induction of GNMT during pregnancy alters methyl group metabolism in the fetus. Non‐diabetic and diabetic (STZ) pregnant rats treated with and without RA, were sacrificed on d 18 of gestation for collection of blood and liver tissue. Two hepatic immunoreactive proteins were clearly detected (32 and ~36 kD) in liver tissue. The lighter form (L‐GNMT) was more responsive in maternal liver, whereas the heavier protein (H‐GNMT) dominated in fetal liver. Rats receiving both RA and STZ exhibited elevated maternal hepatic GNMT activity, L‐GNMT abundance, and DNA hypomethylation, and reduced circulating homocysteine levels. Fetal liver expressed only H‐GNMT which was slightly responsive to treatment; however, L‐GNMT expression was evident in the combined treatment group. Fetal hepatic tissue did not exhibit changes in DNA methylation, due to the lack of L‐GNMT expression.