Maternal smoking during pregnancy is associated with mitochondrial DNA methylation

Abstract

Maternal smoking during pregnancy (MSDP) has detrimental effects on fetal development and on the health of the offspring into adulthood. Energy homeostasis through ATP production via the mitochondria (mt) plays a key role during pregnancy. This study aimed to determine if MSDP resulted in differences in DNA methylation to the placental mitochondrial chromosome at the transcription and replication control region, the D-Loop, and if these differences were also present in an alternate neonatal tissue (foreskin) in an independent birth cohort. We investigated mtDNA methylation by bisulfite-pyrosequencing in two sections of the D-Loop control region and in long interspersed nuclear element-1 (LINE-1) genomic sequences in placenta from 96 mother–newborn pairs that were enrolled in a Rhode Island birth cohort along with foreskin samples from 62 infants from a Kentucky birth cohort. In both placenta and foreskin, mtDNA methylation in the light chain D-Loop region 1 was positively associated with MSDP in placenta (difference+2.73%) (P=0.001) and foreskin (difference+1.22%) (P=0.08). Additionally, in foreskin, a second segment of the D-Loop-heavy chain region 1 showed a small but significant change in methylation with MSDP (+0.4%, P=0.04). No methylation changes were noted in either tissue at the LINE-1 repetitive element. We identified a similar pattern of epigenetic effect to mitochondria arising in cells from different primordial lineages and in different populations, associated with MSDP. These robust and consistent results build evidence that MSDP may impact mt D-Loop methylation, as one mechanism through which this exposure affects newborn health.

Maternal exposure to cigarette smoking induces immediate and durable changes in placental DNA methylation affecting enhancer and imprinting control regions

“…In another study of 379 term placentas, AluYb8 methylation level was significantly higher in smoking women compared to nonsmokers, while no evidence of significant association was found for LINE-1 (60). Another study conducted on 96 term placentas failed to find any association between LINE-1 methylation and maternal smoking (61). These apparent discrepancies with our results could be explained by a lack of statistical power to detect an effect of smoking for the first study and for the other two the fact that the samples were collected preferentially on the maternal side of the placenta, as opposed to our study conducted on samples representing the fetal side of the placenta.…”

Mitochondrial DNA: Epigenetics and environment

“…For example, the exposure of steel workers to PM 10 has been associated with hypermethylation of the MT-TF (phenylalanine tRNA) and MT-RNR1 (12S rRNA) genes in peripheral blood (Byun et al, 2013). Lastly, smoking during pregnancy has been associated with methylation of the placental D-loop region as well as MT-RNR1 gene impacting health of newborns (Armstrong et al, 2016;Janssen et al, 2017). In contrast, the exposure of PM 2.5 , produced from welding, decreases blood mtDNA methylation in the D-loop region (Byun et al, 2016).…”

“…In another study, exposure to fumes from welding has been linked to hypomethylation in the D-loop and MT-TF and increases blood pressure . Lastly, smoking during pregnancy has been associated with methylation of the placental D-loop region as well as MT-RNR1 gene impacting health of newborns (Armstrong et al, 2016;Janssen et al, 2017).…”

Chained Risk Assessment for Life-Long Disease Burden of Early Exposures–Demonstration of Concept Using Prenatal Maternal Smoking

“…Despite public health efforts, maternal smoking remains to be prevalent with 14% of all newborns exposed in Finland in 2015 [16]. Exposure to maternal smoking leads to epigenetic changes in the exposed fetus [16][17][18][19], indicating persistent changes in susceptibility to environmental exposures [5]. Emerging evidence is suggesting DNA methylation as a mechanism for the effect of maternal smoking on birth weight [20].…”