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

Amanda J Drake (Corresponding Author), Peter J O'Shaughnessy, Siladitya Bhattacharya, Ana Monteiro, David Kerrigan, Sven Goetz, Andrea Raab, Stewart M Rhind, Kevin D Sinclair, Andrew A Meharg, Jörg Feldmann, Paul A Fowler

Research output: Contribution to journalArticle

38 Citations (Scopus)
6 Downloads (Pure)

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.

Original languageEnglish
Article number18
JournalBMC medicine
Volume13
DOIs
Publication statusPublished - 29 Jan 2015

Fingerprint

DNA Methylation
Tobacco Products
Carbon
Smoking
Mothers
Liver
Vitamin B 12
Carbon Cycle
Fetus
Homocysteine
Sex Characteristics
Pregnancy
Disease Susceptibility
Glucocorticoid Receptors
Enzymes
Cobalt
Retrospective Studies
Parturition
Messenger RNA
Genes

Keywords

  • DNA methylation
  • liver
  • maternal smoking
  • vitamin B12

Cite this

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 (Corresponding Author); O'Shaughnessy, Peter J; Bhattacharya, Siladitya; Monteiro, Ana; Kerrigan, David; Goetz, Sven; Raab, Andrea; Rhind, Stewart M; Sinclair, Kevin D; Meharg, Andrew A; Feldmann, Jörg; Fowler, Paul A.

In: BMC medicine , Vol. 13, 18, 29.01.2015.

Research output: Contribution to journalArticle

Drake, Amanda J ; O'Shaughnessy, Peter J ; Bhattacharya, Siladitya ; Monteiro, Ana ; Kerrigan, David ; Goetz, Sven ; Raab, Andrea ; Rhind, Stewart M ; Sinclair, Kevin D ; Meharg, Andrew A ; Feldmann, Jörg ; 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. In: BMC medicine . 2015 ; Vol. 13.
@article{9d360ac770954b66bae5aaa22bb73fff,
title = "In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver",
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.",
keywords = "DNA methylation, liver, maternal smoking, vitamin B12",
author = "Drake, {Amanda J} and O'Shaughnessy, {Peter J} and Siladitya Bhattacharya and Ana Monteiro and David Kerrigan and Sven Goetz and Andrea Raab and Rhind, {Stewart M} and Sinclair, {Kevin D} and Meharg, {Andrew A} and J{\"o}rg Feldmann and Fowler, {Paul A}",
note = "This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Acknowledgements: We thank Ms Margaret Fraser, Ms Samantha Flannigan, and Dr Wing Yee Kwong for their expert assistance. The staff at Grampian NHS Pregnancy Counselling Service were essential for collecting fetuses. We thank Professor Geoffrey Hammond and Dr Marc Simard, University of British Colombia for helpful comments on the manuscript. Supported by grants as follows: Scottish Senior Clinical Fellowship (AJD); Chief Scientist Office (Scottish Executive, CZG/1/109 to PAF, & CZG/4/742 (PAF & PJOS); NHS Grampian Endowments 08/02 (PAF, SB & PJOS); the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 212885 (PAF & SMR); the Medical Research Council grants MR/L010011/1 (PAF & PJOS) and MR/K018310/1 (AJD). None of the funding bodies played any role in the design, collection, analysis, and interpretation of data, in the writing of the manuscript, nor in the decision to submit the manuscript for publication",
year = "2015",
month = "1",
day = "29",
doi = "10.1186/s12916-014-0251-x",
language = "English",
volume = "13",
journal = "BMC medicine",
issn = "1741-7015",
publisher = "BioMed Central",

}

TY - JOUR

T1 - In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver

AU - Drake, Amanda J

AU - O'Shaughnessy, Peter J

AU - Bhattacharya, Siladitya

AU - Monteiro, Ana

AU - Kerrigan, David

AU - Goetz, Sven

AU - Raab, Andrea

AU - Rhind, Stewart M

AU - Sinclair, Kevin D

AU - Meharg, Andrew A

AU - Feldmann, Jörg

AU - Fowler, Paul A

N1 - This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Acknowledgements: We thank Ms Margaret Fraser, Ms Samantha Flannigan, and Dr Wing Yee Kwong for their expert assistance. The staff at Grampian NHS Pregnancy Counselling Service were essential for collecting fetuses. We thank Professor Geoffrey Hammond and Dr Marc Simard, University of British Colombia for helpful comments on the manuscript. Supported by grants as follows: Scottish Senior Clinical Fellowship (AJD); Chief Scientist Office (Scottish Executive, CZG/1/109 to PAF, & CZG/4/742 (PAF & PJOS); NHS Grampian Endowments 08/02 (PAF, SB & PJOS); the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 212885 (PAF & SMR); the Medical Research Council grants MR/L010011/1 (PAF & PJOS) and MR/K018310/1 (AJD). None of the funding bodies played any role in the design, collection, analysis, and interpretation of data, in the writing of the manuscript, nor in the decision to submit the manuscript for publication

PY - 2015/1/29

Y1 - 2015/1/29

N2 - 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.

AB - 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.

KW - DNA methylation

KW - liver

KW - maternal smoking

KW - vitamin B12

U2 - 10.1186/s12916-014-0251-x

DO - 10.1186/s12916-014-0251-x

M3 - Article

VL - 13

JO - BMC medicine

JF - BMC medicine

SN - 1741-7015

M1 - 18

ER -