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Biochemical, Molecular, and Genetic Mechanisms

Folic Acid Supplementation during the Juvenile-Pubertal Period in Rats Modifies the Phenotype and Epigenotype Induced by Prenatal Nutrition^1–3,

⁴ Institute of Human Nutrition, ⁵ Development and Cell Biology, and ⁶ Institute of Developmental Sciences, University of Southampton, Southampton SO16 6YD, UK

Prenatal nutritional constraint is associated with increased risk of metabolic dysregulation in adulthood contingent on adult diet. In rats, folic acid supplementation of a protein-restricted (PR) diet during pregnancy prevents altered phenotype and epigenotype in the offspring induced by the PR diet. We hypothesized that increasing folic acid intake during the juvenile-pubertal (JP) period would reverse the effects of a maternal PR diet on the offspring. Rats were fed a control (C) or PR diet during pregnancy and AIN93G during lactation. Offspring were weaned on d 28 onto diets containing 1 mg [adequate folate (AF)] or 5 mg [folic acid-supplemented (FS)] folic acid/kg feed. After 28 d, all offspring were fed a high-fat (18% wt:wt) diet and killed on d 84. As expected, offspring of PR dams fed the AF diet had increased fasting plasma triglyceride (TAG) and β-hydroxybutyrate (βHB) concentrations. The FS diet induced increased weight gain, a lower plasma βHB concentration, and increased hepatic and plasma TAG concentration compared with AF offspring irrespective of maternal diet. PPAR and glucocorticoid receptor promoter methylation increased in liver and insulin receptor promoter methylation decreased in liver and adipose tissue in FS compared with AF offspring, with reciprocal changes in mRNA expression irrespective of maternal diet. These findings show that increased folic acid intake during the JP period did not simply reverse the phenotype induced by the maternal diet. This may represent a period of plasticity when specific nutrient intakes may alter the phenotype of the offspring through epigenetic changes in specific genes.

^* To whom correspondence should be addressed. E-mail: g.c.burdge{at}southampton.ac.uk

Manuscript received 14 January 2009. Initial review completed 24 February 2009. Revision accepted 5 March 2009.

Published online 1 April 2009.

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