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In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver

Drake, Amanda J.; O'Shaughnessy, Peter J.; Bhattachyrya, Siladitya; Monteiro, Ana; Kerrigan, David; Goetz, Sven; Raab, Andrea; Rhind, Stewart M.; Sinclair, Kevin D.; Meharg, Andrew A.; Feldmann, Jorg; Fowler, Paul A.

Authors

Amanda J. Drake

Peter J. O'Shaughnessy

Siladitya Bhattachyrya

Ana Monteiro

David Kerrigan

Sven Goetz

Andrea Raab

Stewart M. Rhind

KEVIN SINCLAIR kevin.sinclair@nottingham.ac.uk
Professor of Developmental Biology

Andrew A. Meharg

Jorg Feldmann

Paul A. Fowler



Abstract

Background: 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. 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.
Methods: In 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. Results: In 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).
Conclusions: Our 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.

Journal Article Type Article
Publication Date Jan 29, 2015
Journal BMC Medicine
Electronic ISSN 1741-7015
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 13
APA6 Citation Drake, A. J., O'Shaughnessy, P. J., Bhattachyrya, S., Monteiro, A., Kerrigan, D., Goetz, S., …Fowler, P. A. (2015). In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver. BMC Medicine, 13, https://doi.org/10.1186/s12916-014-0251-x
DOI https://doi.org/10.1186/s12916-014-0251-x
Keywords DNA methylation, Liver, Maternal smoking, Vitamin B12
Publisher URL http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-014-0251-x
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0


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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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