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

Drake, A. J. et al. (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(18), (doi:10.1186/s12916-014-0251-x)

[img]
Preview
Text
103533.pdf - Published Version
Available under License Creative Commons Attribution.

2MB
[img]
Preview
Text
103533(1).pdf - Cover Image

61kB

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Monteiro, Dr Ana and O'Shaughnessy, Professor Peter
Authors: Drake, A. J., O'Shaughnessy, P. J., Bhattacharya, S., Monteiro, A., Kerrigan, D., Goetz, S., Raab, A., Rhind, S. M., Sinclair, K. D., Meharg, A. A., Feldmann, J., and Fowler, P. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:BMC Medicine
Publisher:BioMed Central
ISSN:1741-7015
ISSN (Online):1741-7015
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in BMC Medicine 13:18
Publisher Policy:Reproduced under a Creative Commons License
Related URLs:

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
519942Bio-incubator system to model toxic effects on the human fetal testisPeter O'ShaughnessyScottish Executive Health Department (SEHHD-CSO)CZB/4/742RI BIODIVERSITY ANIMAL HEALTH & COMPMED