DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status.
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.
School of Biosciences and School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Leicestershire LE12 5RD, United Kingdom.
Kevin D
KD
Sinclair
Cinzia
C
Allegrucci
Ravinder
R
Singh
David S
DS
Gardner
Sonia
S
Sebastian
Jayson
J
Bispham
Alexandra
A
Thurston
John F
JF
Huntley
William D
WD
Rees
Christopher A
CA
Maloney
Richard G
RG
Lea
Jim
J
Craigon
Tom G
TG
McEvoy
Lorraine E
LE
Young
D000818:Animals; D000831:Animals, Newborn / Q000276:immunology / Q000378:metabolism; D001794:Blood Pressure; D001823:Body Composition / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D004032:Diet; D004622:Embryo, Mammalian / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D005306:Fertilization; D005492:Folic Acid / Q000008:administration & dosage; D005947:Glucose / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D007109:Immunity; D007333:Insulin Resistance; D008715:Methionine / Q000008:administration & dosage*; D011247:Pregnancy / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011256:Pregnancy Outcome; D012756:Sheep / Q000196:embryology / Q000378:metabolism; D014805:Vitamin B 12 / Q000008:administration & dosage; D014803:Vitamin B Complex / Q000008:administration & dosage*
D014803:Vitamin B Complex; D005492:Folic Acid; D008715:Methionine; D005947:Glucose; D014805:Vitamin B 12