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Background  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.    Methods  In the framework of the ENVIR ON AGE 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.    Results  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.    Conclusions  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.    Electronic supplementary material  The online version of this article (doi:10.1186/s12967-016-1113-4) contains supplementary material, which is available to authorized users.

journal of translational medicine

Placental mitochondrial DNA and CYP1A1 gene methylation as molecular signatures for tobacco smoke exposure in pregnant women and the relevance for birth weight