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; 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

doi:10.1186/s12916-014-0251-x

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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 language	English
Article number	18
Number of pages	12
Journal	BMC medicine
Volume	13
DOIs	https://doi.org/10.1186/s12916-014-0251-x
Publication status	Published - 29 Jan 2015

Bibliographical 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

Keywords

DNA methylation
liver
maternal smoking
vitamin B12

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s12916-014-0251-xLicence: CC BY

Drake et al BMCMed15 inutero cigarette sex specific 1C methylation human fetal liver plus sup
© 2015 Drake et al.; licensee BioMed Central. 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.
Final published version, 2.44 MBLicence: CC BY

Jörg Feldmann
- School of Natural & Computing Sciences, Chemistry - Honorary Lecturer
Person: Honorary
Paul Alfred François Fowler
- School of Medicine, Medical Sciences & Nutrition, Molecular and Cellular Function
- School of Medicine, Medical Sciences & Nutrition, Applied Medicine - Chair in Translational Medical Sciences
- School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences
Person: Academic

Cite this

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., & 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, [18]. https://doi.org/10.1186/s12916-014-0251-x

Drake, AJ, O'Shaughnessy, PJ, Bhattacharya, S, Monteiro, A, Kerrigan, D, Goetz, S, Raab, A, Rhind, SM, Sinclair, KD, Meharg, AA, Feldmann, J & Fowler, PA 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 , vol. 13, 18. https://doi.org/10.1186/s12916-014-0251-x

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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",

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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{\textquoteright}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",

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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

C2 - 25630355

SN - 1741-7015

VL - 13

JO - BMC medicine

JF - BMC medicine

M1 - 18

ER -

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

Abstract

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Jörg Feldmann

Paul Alfred François Fowler

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