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

Abstract

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 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-loopand 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 CYP1A1in 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 CYP1A1methylation 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 CYP1A1methylation in placental tissue may serve as molecular signatures for the association between gestational tobacco smoke exposure and low birth weight.