DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status

TLDR

Adult health disorders can originate from developmental events in utero, the periconceptional period is programmable, and DNA methylation—dependent on dietary methyl groups—plays a key epigenetic role. The study aimed to test whether restricting B12, folate, and methionine during the periconceptional period would epigenetically alter DNA methylation in early embryos and affect offspring health. The authors restricted B12, folate, and methionine in the periconceptional diet of mature female sheep within normal ranges to assess effects on offspring. The dietary restriction had no impact on pregnancy or birth weight but produced adult offspring that were heavier, fatter, insulin‑resistant, had higher blood pressure (especially males), and displayed altered immune responses; genome‑wide methylation analysis revealed changes in 4 % of CpG islands, predominantly male‑specific, demonstrating that modest periconceptional reductions in methionine/folate can program widespread epigenetic alterations and adult health outcomes.

Abstract

A complex combination of adult health-related disorders can originate from developmental events that occur in utero . The periconceptional period may also be programmable. We report on the effects of restricting the supply of specific B vitamins (i.e., B 12 and folate) and methionine, within normal physiological ranges, from the periconceptional diet of mature female sheep. We hypothesized this would lead to epigenetic modifications to DNA methylation in the preovulatory oocyte and/or preimplantation embryo, with long-term health implications for offspring. DNA methylation is a key epigenetic contributor to maintenance of gene silencing that relies on a dietary supply of methyl groups. We observed no effects on pregnancy establishment or birth weight, but this modest early dietary intervention led to adult offspring that were both heavier and fatter, elicited altered immune responses to antigenic challenge, were insulin-resistant, and had elevated blood pressure–effects that were most obvious in males. The altered methylation status of 4% of 1,400 CpG islands examined by restriction landmark genome scanning in the fetal liver revealed compelling evidence of a widespread epigenetic mechanism associated with this nutritionally programmed effect. Intriguingly, more than half of the affected loci were specific to males. The data provide the first evidence that clinically relevant reductions in specific dietary inputs to the methionine/folate cycles during the periconceptional period can lead to widespread epigenetic alterations to DNA methylation in offspring, and modify adult health-related phenotypes.