Abstract
BackgroundMaternal 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.MethodsIn 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.ResultsSmokers 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.ConclusionsmtDNA 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.
Highlights
Maternal smoking during pregnancy results in an increased risk of low birth weight through pertur‐ bations in the utero-placental exchange
Constituents of tobacco smoke such as polycyclic aromatic hydrocarbons (PAHs) enter cells and may activate genes involved in detoxification processes such as cytochrome P450 (CYP1A1) via the aryl hyrdrocarbon receptor (Ahr) signaling pathway resulting in an oxidative imbalance of the cells
Global [15,16,17,18] and gene-specific (e.g. CYP1A1) [19,20,21,22,23,24,25,26] DNA methylation differences have been demonstrated in cord blood and placental cells of neonates from mothers who smoked during pregnancy
Summary
Maternal smoking during pregnancy results in an increased risk of low birth weight through pertur‐ bations in the utero-placental exchange. Epigenetics and mitochondrial function in fetal tissues might be molecular signatures responsive to in utero tobacco smoke exposure. It is well known that maternal smoking during pregnancy increases the risk of low birth weight [1, 2] and preterm delivery [3, 4] which is probably due to perturbations in the fetoplacental exchange [5]. The exact mechanism(s) underlying these adverse effects remain unclear, but emerging data suggests that biochemical, genetic, and epigenetic processes respond to and/or are modified by in utero tobacco exposure of the fetal organism. Growing evidence suggests that mitochondrial dysfunction may affect the epigenetic landscape of the nuclear genome [11, 12]. Disruption of the fetal methylome has been associated with adverse pregnancy outcomes and could provide an underlying mechanism through which smoking affects fetal growth [20, 24, 27]
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