DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status - PubMed (original) (raw)

. 2007 Dec 4;104(49):19351-6.

doi: 10.1073/pnas.0707258104. Epub 2007 Nov 27.

Cinzia Allegrucci, Ravinder Singh, David S Gardner, Sonia Sebastian, Jayson Bispham, Alexandra Thurston, John F Huntley, William D Rees, Christopher A Maloney, Richard G Lea, Jim Craigon, Tom G McEvoy, Lorraine E Young

Affiliations

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

Kevin D Sinclair et al. Proc Natl Acad Sci U S A. 2007.

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Innate and adaptive immune responses to ovalbumin in Quil A adjuvant determined in offspring, derived from the embryos of ewes offered either a control or MD diet, at 1 year of age. (A) Acute-phase (serum haptoglobin) response measured over a 48-h period after the initial vaccination. (B) Serum IgG measured at weekly intervals over 9 weeks, during which time additional boluses of ovalbumin were administered at weeks 3 and 6. Error bars are SED.

Fig. 2.

Fig. 2.

Cardiovascular function in offspring, derived from the embryos of ewes offered either a control or MD diet, at 23 months of age. (A) Resting, body-fat-adjusted systolic, diastolic, and mean arterial blood pressure. (B) Change in systolic blood pressure during angiotensin II infusion. Values are minute means for a baseline period of 10 min (adjusted to zero), followed by 1 h of angiotensin II infusion (increments from 2.5 to 60 ng·kg−1·min−1 every 10 min) and 10 min of recovery. Error bars are SEM.

Fig. 3.

Fig. 3.

RLGS profile of sheep liver at fetal day 90. (A) Spots present in the representative autoradiograph represent unmethylated CpG sites in the genome that are digested with the methylation-sensitive enzyme NotI. The first-dimension separation of RLGS fragments (NotI/EcoRV) extends horizontally, whereas the second dimension (NotI/HinfI) extends vertically in the profile. (B) Enlarged representation of quadrant 2B in the master profile, for which letters/numbers allocated to each RLGS fragment have been assigned. (C) Example methylation differences observed between control and MD individuals. RLGS fragment 1D04 represents a methylation event, with spots disappearing from the profile; fragments 1CZB and 1CE represent demethylation events, with spots appearing in the profile.

Fig. 4.

Fig. 4.

RLGS of DNA methylation differences between control and MD liver at fetal day 90. (A) The unique identifier codes (locus) of fragments that varied between each MD individual and all of the controls are shown. RLGS fragments that varied among control-group individuals were not scored to minimize scoring of genetic polymorphisms as DNA methylation differences. “Control” indicates whether each locus was methylated (M) or unmethylated (U) in the control group. Data representing the loci that differed from the control group in 2–11 MD individuals are presented in ascending order. Blue boxes indicate loci methylated in the indicated MD individuals and unmethylated in all controls. Purple boxes indicate MD loci unmethylated in MD individuals and methylated in controls. Orange boxes indicate MD loci hypomethylated in MD individuals. (B) Summary of methylation differences between the control group and the MD individuals.

References

    1. Barker DJ. Eur J Clin Invest. 1995;25:457–463. - PubMed
    1. McMillen IC, Robinson JS. Physiol Rev. 2005;85:571–633. - PubMed
    1. Langley-Evans SC. Proc Nutr Soc. 2006;65:97–105. - PMC - PubMed
    1. Sinclair KD, Singh R. Theriogenology. 2007;67:43–53. - PubMed
    1. Underwood EJ, Suttle NF. The Mineral Nutrition of Livestock. 3rd Ed. Oxon, UK: CAB International; 1999.

Publication types

MeSH terms

Substances

LinkOut - more resources