Gender-specific methylation differences in relation to prenatal exposure to cigarette smoke.
Epigenetic alterations may mechanistically explain the developmental origins of adult disease, namely the hypothesis that many complex adult chronic diseases originate as a result of conditions encountered in utero. If true, epigenetically regulated imprinted genes, critical to normal growth and development, may partially mediate these outcomes. We determined the influence of in utero exposure to cigarette smoking on methylation at two differentially methylated regions (DMRs) regulating Insulin-like Growth Factor 2 (IGF2) and H19, and how this might relate to birth weight of infants born to 418 pregnant women. Smoking status was ascertained through self-report and medical records. Bisulfite pyrosequencing was used to measure methylation in umbilical cord blood DNAs. Least squares DNA methylation means at each DMR and birth weight were compared between infants of smokers and non-smokers, using generalized linear models. While there were no significant differences at the H19 DMR, infants born to smokers had higher methylation at the IGF2 DMR than those born to never smokers or those who quit during pregnancy (49.5%, SD=8.0 versus 46.6%, SD=5.6 and 45.8%, SD=6.3, respectively; p=0.0002). The smoking-related increase in methylation was most pronounced in male offspring (p for sex interaction=0.03), for whom approximately 20% of smoking-related low birth weight was mediated by DNA methylation at the IGF2 DMR. Our findings suggest that IGF2 DMR plasticity is an important mechanism by which in utero adjustments to environmental toxicants are conferred. Larger studies to replicate these findings are required.
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC 27708, USA. susan.murphy@duke.edu
Susan K
SK
Murphy
Abayomi
A
Adigun
Zhiqing
Z
Huang
Francine
F
Overcash
Frances
F
Wang
Randy L
RL
Jirtle
Joellen M
JM
Schildkraut
Amy P
AP
Murtha
Edwin S
ES
Iversen
Cathrine
C
Hoyo
D000328:Adult; D001724:Birth Weight; D019175:DNA Methylation; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D012727:Sex Characteristics; D012907:Smoking / Q000235:genetics*
C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II