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.
authors: Endocrinology Unit, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. mandy.drake@ed.ac.uk.
authors: Amanda J
authors: AJ
authors: Drake
authors: Peter J
authors: PJ
authors: O'Shaughnessy
authors: Siladitya
authors: S
authors: Bhattacharya
authors: Ana
authors: A
authors: Monteiro
authors: David
authors: D
authors: Kerrigan
authors: Sven
authors: S
authors: Goetz
authors: Andrea
authors: A
authors: Raab
authors: Stewart M
authors: SM
authors: Rhind
authors: Kevin D
authors: KD
authors: Sinclair
authors: Andrew A
authors: AA
authors: Meharg
authors: Jörg
authors: J
authors: Feldmann
authors: Paul A
authors: PA
authors: Fowler
mesh_terms: D000328:Adult; D001835:Body Weight; D002244:Carbon / Q000378:metabolism*; D003035:Cobalt / Q000032:analysis; D019175:DNA Methylation / Q000187:drug effects*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D019875:One-Carbon Group Transferases / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012189:Retrospective Studies; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects*; D014805:Vitamin B 12 / Q000032:analysis
chemical_list: C035170:IGF2 protein, human; C497713:NR3C1 protein, human; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D003035:Cobalt; D007335:Insulin-Like Growth Factor II; D002244:Carbon; D019875:One-Carbon Group Transferases; D014805:Vitamin B 12
references: Clin Epigenetics. 2011 Oct 26;3:2
references: 22414206
references: Hum Mol Genet. 2012 Jul 1;21(13):3073-82
references: 22492999
references: Epigenetics. 2011 Feb;6(2):171-6
references: 20930547
references: Diabetologia. 2008 Jan;51(1):29-38
references: 17851649
references: Biol Reprod. 2002 Apr;66(4):966-75
references: 11906915
references: Mol Hum Reprod. 2013 Mar;19(3):177-87
references: 23197595
references: J Mol Endocrinol. 2005 Oct;35(2):283-92
references: 16216909
references: Reproduction. 2013 Jan;145(1):R1-13
references: 23081892
references: J Clin Endocrinol Metab. 2007 Dec;92(12):4792-801
references: 17848411
references: Cancer Epidemiol Biomarkers Prev. 2008 Sep;17(9):2306-10
references: 18768498
references: Gene. 2012 Feb 15;494(1):36-43
references: 22202639
references: Cancer Epidemiol Biomarkers Prev. 2011 Dec;20(12):2518-23
references: 21994404
references: Hum Mol Genet. 2009 Nov 1;18(21):4046-53
references: 19656776
references: J Clin Endocrinol Metab. 2008 Feb;93(2):619-26
references: 18000085
references: J Clin Endocrinol Metab. 2005 May;90(5):2556-62
references: 15713720
references: Pediatrics. 2001 Sep;108(3):624-30
references: 11533328
references: Paediatr Perinat Epidemiol. 2000 Apr;14(2):118-26
references: 10791654
references: Pediatr Res. 2008 Jun;63(6):593-8
references: 18317238
references: Dev Biol. 2008 Aug 1;320(1):79-91
references: 18550048
references: Clin Endocrinol (Oxf). 2012 Dec;77(6):808-15
references: 22642564
references: Eur J Clin Nutr. 2006 Jun;60(6):791-801
references: 16404414
references: Genesis. 2006 Sep;44(9):401-6
references: 16868943
references: Anal Biochem. 2004 Oct 1;333(1):119-27
references: 15351288
references: Anal Bioanal Chem. 2008 Apr;390(7):1739-51
references: 18084749
references: Reproduction. 2001 Aug;122(2):227-34
references: 11467973
references: Epigenetics. 2008 Mar-Apr;3(2):97-106
references: 18536531
references: Cell. 1991 Feb 22;64(4):849-59
references: 1997210
references: Hum Reprod Update. 2013 Nov-Dec;19(6):640-55
references: 23959022
references: Food Nutr Bull. 2008 Dec;29(4):249-54
references: 19227049
references: Eur J Pediatr. 2006 Nov;165(11):757-61
references: 16775725
references: Environ Health Perspect. 2012 Oct;120(10):1425-31
references: 22851337
references: PLoS One. 2012;7(7):e41106
references: 22829913
references: PLoS One. 2013;8(12):e81731
references: 24349121
references: Biol Neonate. 2004;85(4):249-55
references: 14739552
references: Epigenetics. 2009 Aug 16;4(6):394-8
references: 19755846
references: Clin Chem. 1999 Feb;45(2):290-2
references: 9931056
references: Eur J Obstet Gynecol Reprod Biol. 2002 Jun 10;103(1):18-21
references: 12039457
references: Epigenetics. 2014 Mar;9(3):377-86
references: 24270552
references: Lancet. 1986 May 10;1(8489):1077-81
references: 2871345
references: Hum Mol Genet. 2012 May 1;21(9):2086-101
references: 22307237
references: Mol Cell Biol. 2003 Aug;23(15):5293-300
references: 12861015
references: PLoS One. 2012;7(3):e33290
references: 22479380
references: J Nutr. 2005 Jun;135(6):1382-6
references: 15930441
references: Subst Abuse Treat Prev Policy. 2010;5:1
references: 20092650
references: EMBO J. 2001 Apr 17;20(8):1974-83
references: 11296230
references: Int J Obes Relat Metab Disord. 2004 Nov;28(11):1494-502
references: 15326465
references: Nat Neurosci. 2004 Aug;7(8):847-54
references: 15220929
references: Proc Natl Acad Sci U S A. 2012 Oct 16;109 Suppl 2:17253-60
references: 23045638
references: Development. 1994 Oct;120(10):2933-43
references: 7607083
references: Endocrinology. 2010 Apr;151(4):1581-7
references: 20133452
references: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19351-6
references: 18042717
references: Int J Mol Med. 2011 Oct;28(4):481-7
references: 21805044
references: Placenta. 2010 Mar;31(3):197-202
references: 20060582
references: Nat Neurosci. 2009 Mar;12(3):342-8
references: 19234457
references: PLoS One. 2008;3(3):e1849
references: 18365005
references: Biol Reprod. 2009 Apr;80(4):743-52
references: 19074000
references: Am J Respir Crit Care Med. 2009 Sep 1;180(5):462-7
references: 19498054
references: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17046-9
references: 18955703
references: Epigenetics. 2012 Mar;7(3):253-60
references: 22430801
references: J Clin Endocrinol Metab. 2011 Sep;96(9):2851-60
references: 21715529
references: Hum Mol Genet. 2007 Mar 1;16(5):547-54
references: 17339271