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

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., B12 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 healthrelated phenotypes. E vidence from both epidemiological studies in humans and direct intervention studies in animals indicates that altering key developmental processes in utero can predispose offspring to many late-onset diseases such as dyslipidemia, type II diabetes, and heart disease (1, 2). In this regard, the effects of gross nutrient or protein deficiencies in maternal diet during pregnancy are well documented (3), although little is known about the effects of specific nutrients or the timing and mechanistic basis of nutrient programming (4). Here we investigated the effects of restricting the supply of specific B group vitamins (i.e., vitamin B 12 and folate) and sulfur amino acids (in particular, methionine) from the diet of adult female sheep from 8 weeks preceding until 6 days after conception, within physiological ranges encountered in both sheep (5) and humans (i.e., within the 5th and 95th percentiles) (6, 7). These micronutrients are important intermediates and/or have specific regulatory functions in the linked methionine-folate cycles (5, 7). In rodents, maternal supraphysiological methyl group supply and a low-protein diet (50% control) offered throughout pregnancy altered DNA methylation of candidate genes (agouti, glucocorticoid receptor, and peroxisomal proliferator-activated receptor-␣) (8, 9), but the extent of methylation change in these or more clinically relevant diets is not known. Gametes and preimplantation emb...

Exposure of neonatal rats to maternal cafeteria feeding during suckling alters hepatic gene expression and DNA methylation in the insulin signalling pathway

“…It is of interest that this effect was seen only in males. Sex Sinclair et al (2007) who similarly reported sensitivity of DNA methylation to maternal diet in males, but not females. As crude global methylation changes would be insufficient evidence that the diet impacted upon the genome, it is important to note that IrB was the a specific gene target for which an effect of the diet upon DNA methylation was noted.…”

“…There is good evidence from animal models of undernutrition during foetal life that maternal diet can alter the epigenome, particularly DNA methylation, and this may establish changes in gene expression that permanently modify tissue structure or reset the responses to dietary and age-related challenges that occur later in life (Sinclair et al 2007;Lillycrop et al 2007;Bogdarina et al 2010). Exposure to high-fat diets has been shown to alter DNA methylation and histone marks in rodents, non-human primates and primates, with the brain being particularly sensitive to dietary influences (Seki et al 2012;Carlin et al 2013;Langie et al 2013;Jacobsen et al 2012).…”

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

“…However, until now, few studies have associated perinatal methyl donors with long-term changes in body weight and metabolism. In sheep, low periconceptional supply of vitamin B12 and folate has been associated to fatter adult offspring, insulin-resistance and elevated blood pressure, which was accompanied by widespread epigenetic alterations to DNA methylation (Sinclair et al, 2007). In rats, perinatal methyl donor deficiency induces modest changes in the insulin axis of the fetus (Maloney et al, 2009) and programs glucose homeostasis in adult male but not female offspring (Maloney et al, 2011).…”

Epigenetics and developmental programming of welfare and production traits in farm animals

“…Altered nutrition during gametogenesis and preimplantation development, shown to modulate DNA methylation patterns (e.g. Sinclair et al 2007), may augment sexual dimorphism of gene expression patterns and thereby contribute to more pronounced gender differences in adult animals.…”