Abstract
BackgroundMaternal smoking is one of the most important modifiable risk factors for low birthweight, which is strongly associated with increased cardiometabolic disease risk in adulthood. Maternal smoking reduces the levels of the methyl donor vitamin B12 and is associated with altered DNA methylation at birth. Altered DNA methylation may be an important mechanism underlying increased disease susceptibility; however, the extent to which this can be induced in the developing fetus is unknown.MethodsIn this retrospective study, we measured concentrations of cobalt, vitamin B12, and mRNA transcripts encoding key enzymes in the 1-carbon cycle in 55 fetal human livers obtained from 11 to 21 weeks of gestation elective terminations and matched for gestation and maternal smoking. DNA methylation was measured at critical regions known to be susceptible to the in utero environment. Homocysteine concentrations were analyzed in plasma from 60 fetuses.ResultsIn addition to identifying baseline sex differences, we found that maternal smoking was associated with sex-specific alterations of fetal liver vitamin B12, plasma homocysteine and expression of enzymes in the 1-carbon cycle in fetal liver. In the majority of the measured parameters which showed a sex difference, maternal smoking reduced the magnitude of that difference. Maternal smoking also altered DNA methylation at the imprinted gene IGF2 and the glucocorticoid receptor (GR/NR3C1).ConclusionsOur unique data strengthen studies linking in utero exposures to altered DNA methylation by showing, for the first time, that such changes are present in fetal life and in a key metabolic target tissue, human fetal liver. Furthermore, these data propose a novel mechanism by which such changes are induced, namely through alterations in methyl donor availability and changes in 1-carbon metabolism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-014-0251-x) contains supplementary material, which is available to authorized users.
Highlights
Maternal smoking is one of the most important modifiable risk factors for low birthweight, which is strongly associated with increased cardiometabolic disease risk in adulthood
The availability of methyl donors and 1-carbon substrates and co-factors, such as vitamin B12, during pregnancy is associated with differences in DNA methylation in the offspring [12,13], and this may be relevant to humans [14,15]
Our findings that maternal smoking is associated with effects on DNA methylation strengthen and extend previous studies by showing that such changes are detectable in the fetal liver, a major target organ for developmental programming effects [39,40], and that they are present during early development
Summary
Maternal smoking is one of the most important modifiable risk factors for low birthweight, which is strongly associated with increased cardiometabolic disease risk in adulthood. Exposure to an adverse environment in utero leading to a reduction in birthweight is associated with a marked increase in later susceptibility to cardiometabolic and neuroendocrine disorders [1]. One potential pathway by which exposure to adverse environmental conditions, including cigarette smoke in utero, might impact on DNA methylation is through altered availability of methyl donors provided by the 1-carbon pathway [11]. The availability of methyl donors and 1-carbon substrates and co-factors, such as vitamin B12, during pregnancy is associated with differences in DNA methylation in the offspring [12,13], and this may be relevant to humans [14,15]. Maternal vitamin B12, a key co-factor in the 1-carbon cycle, is the major determinant of neonatal vitamin B12 concentrations [16] and maternal smoking reduces the concentrations of vitamin B12 in pregnant women [17] and their infants [18]
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