title: Placental mitochondrial methylation and exposure to airborne particulate matter in the early life environment: An ENVIRONAGE birth cohort study.
abstract: Most research to date has focused on epigenetic modifications in the nuclear genome, with little attention devoted to mitochondrial DNA (mtDNA). Placental mtDNA content has been shown to respond to environmental exposures that induce oxidative stress, including airborne particulate matter (PM). Damaged or non-functioning mitochondria are specifically degraded through mitophagy, exemplified by lower mtDNA content, and could be primed by epigenetic modifications in the mtDNA. We studied placental mtDNA methylation in the context of the early life exposome. We investigated placental tissue from 381 mother-newborn pairs that were enrolled in the ENVIRONAGE birth cohort. We determined mtDNA methylation by bisulfite-pyrosequencing in 2 regions, i.e., the D-loop control region and 12S rRNA (MT-RNR1), and measured mtDNA content by qPCR. PM2.5 exposure was calculated for each participant's home address using a dispersion model. An interquartile range (IQR) increment in PM2.5 exposure over the entire pregnancy was positively associated with mtDNA methylation (MT-RNR1: +0.91%, P = 0.01 and D-loop: +0.21%, P = 0.05) and inversely associated with mtDNA content (relative change of -15.60%, P = 0.001) in placental tissue. mtDNA methylation was estimated to mediate 54% [P = 0.01 (MT-RNR1)] and 27% [P = 0.06 (D-loop)] of the inverse association between PM2.5 exposure and mtDNA content. This study provides new insight into the mechanisms of altered mitochondrial function in the early life environment. Epigenetic modifications in the mitochondrial genome, especially in the MT-RNR1 region, substantially mediate the association between PM2.5 exposure during gestation and placental mtDNA content, which could reflect signs of mitophagy and mitochondrial death.
authors.affiliation: a Centre for Environmental Sciences; Hasselt University ; Diepenbeek , Belgium.
authors.forename: Bram G
authors.initials: BG
authors.lastname: Janssen
authors.forename: Hyang-Min
authors.initials: HM
authors.lastname: Byun
authors.forename: Wilfried
authors.initials: W
authors.lastname: Gyselaers
authors.forename: Wouter
authors.initials: W
authors.lastname: Lefebvre
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Baccarelli
authors.forename: Tim S
authors.initials: TS
authors.lastname: Nawrot
mesh_terms: D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D004781:Environmental Exposure; D044127:Epigenesis, Genetic; D005260:Female; D054629:Genome, Mitochondrial / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D052638:Particulate Matter / Q000633:toxicity; D010920:Placenta / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D012335:RNA, Ribosomal / Q000235:genetics*
chemical_list: D052638:Particulate Matter; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S
keywords: 12S rRNA, Mitochondrial ribosomal 12S rRNA; D-loop, Displacement loop; DNA methylation; IQR, Interquartile range; MT-RNR1, Mitochondrial region RNR1; PM, Particulate matter; air pollution; epigenetics; mitochondria; mitochondrial DNA content; mitochondrial DNA methylation; mtDNA, Mitochondrial DNA; mtDNMT1, Mitochondrial isoform of nuclear-encoded DNA methyltransferase enzyme 1; particulate matter; placenta