In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver
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 methyla...
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| Format: | Article |
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BioMed Central
2015
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| Online Access: | https://eprints.nottingham.ac.uk/38472/ |
| _version_ | 1848795619493150720 |
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| author | 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. |
| author_facet | 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. |
| author_sort | Drake, Amanda J. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:34:58Z |
| format | Article |
| id | nottingham-38472 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:34:58Z |
| publishDate | 2015 |
| publisher | BioMed Central |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-384722020-05-04T17:00:00Z https://eprints.nottingham.ac.uk/38472/ 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. 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. BioMed Central 2015-01-29 Article PeerReviewed 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 and Fowler, Paul 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 . pp. 18-30. ISSN 1741-7015 DNA methylation Liver Maternal smoking Vitamin B12 http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-014-0251-x doi:10.1186/s12916-014-0251-x doi:10.1186/s12916-014-0251-x |
| spellingShingle | DNA methylation Liver Maternal smoking Vitamin B12 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. In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver |
| title | In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver |
| title_full | In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver |
| title_fullStr | In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver |
| title_full_unstemmed | In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver |
| title_short | In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver |
| title_sort | in utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and dna methylation in the human fetal liver |
| topic | DNA methylation Liver Maternal smoking Vitamin B12 |
| url | https://eprints.nottingham.ac.uk/38472/ https://eprints.nottingham.ac.uk/38472/ https://eprints.nottingham.ac.uk/38472/ |