title: Placental mitochondrial DNA and CYP1A1 gene methylation as molecular signatures for tobacco smoke exposure in pregnant women and the relevance for birth weight.
abstract: Maternal smoking during pregnancy results in an increased risk of low birth weight through perturbations in the utero-placental exchange. Epigenetics and mitochondrial function in fetal tissues might be molecular signatures responsive to in utero tobacco smoke exposure.
  
  
  
  In the framework of the ENVIRONAGE birth cohort, we investigated the effect of self-reported tobacco smoke exposure during pregnancy on birth weight and the relation with placental tissue markers such as, (1) relative mitochondrial DNA (mtDNA) content as determined by real-time quantitative PCR, (2) DNA methylation of specific loci ﻿of mtDNA (D-loop and MT-RNR1), and (3) DNA methylation of the biotransformation gene CYP1A1 (the last two determined by bisulfite-pyrosequencing). The total pregnant mother sample included 255 non-smokers, 65 former-smokers who had quit smoking before pregnancy, and 62 smokers who continued smoking during pregnancy.
  
  
  
  Smokers delivered newborns with a birth weight on average 208 g lower [95% confidence interval (CI) -318 to -99, p = 0.0002] than mothers who did not smoke during pregnancy. In the smoker group, the relative mtDNA content was lower (-21.6%, 95% CI -35.4 to -4.9%, p = 0.01) than in the non-smoker group; whereas, absolute mtDNA methylation levels of MT-RNR1 were higher (+0.62%, 95% CI 0.21 to 1.02%, p = 0.003). Lower CpG-specific methylation of CYP1A1 in placental tissue (-4.57%, 95% CI -7.15 to -1.98%, p < 0.0001) were observed in smokers compared with non-smokers. Nevertheless, no mediation of CYP1A1 methylation nor any other investigated molecular signature was observed for the association between tobacco smoke exposure and birth weight.
  
  
  
  mtDNA content, methylation of speci﻿fic loci of mtDNA, and CYP1A1 methylation in placental tissue may serve as molecular signatures for the association between gestational tobacco smoke exposure and low birth weight.
authors.affiliation: Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium.
authors.forename: Bram G
authors.initials: BG
authors.lastname: Janssen
authors.affiliation: Department of Obstetrics, East-Limburg Hospital, Genk, Belgium.|Department of Physiology, Hasselt University, Diepenbeek, Belgium.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Gyselaers
authors.affiliation: Laboratory of Environmental Epigenetics, Exposure Epidemiology and Risk Program, Harvard School of Public Health, Boston, MA, 02215, USA.
authors.forename: Hyang-Min
authors.initials: HM
authors.lastname: Byun
authors.affiliation: Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium.|Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Harry A
authors.initials: HA
authors.lastname: Roels
authors.affiliation: Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Cuypers
authors.affiliation: Laboratory of Environmental Epigenetics, Exposure Epidemiology and Risk Program, Harvard School of Public Health, Boston, MA, 02215, USA.|Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA.
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Baccarelli
authors.affiliation: Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium. Tim.Nawrot@uhasselt.be.|Department of Public Health & Primary Care, Occupational and Environmental Medicine, Leuven University, Louvain, Belgium. Tim.Nawrot@uhasselt.be.|Centre for Environmental Sciences, Hasselt University, Agoralaan Gebouw D, 3590, Diepenbeek, Belgium. Tim.Nawrot@uhasselt.be.
authors.forename: Tim S
authors.initials: TS
authors.lastname: Nawrot
mesh_terms: D000328:Adult; D001724:Birth Weight / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003710:Demography; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008019:Life Style; D008297:Male; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012680:Sensitivity and Specificity; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D004272:DNA, Mitochondrial; D014028:Tobacco Smoke Pollution; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1
keywords: Birth weight; CYP1A1; DNA methylation; Epigenetics; Mitochondrial DNA content; Mitochondrial DNA methylation; Placental tissue; Tobacco smoke