DNA methylation links prenatal smoking exposure to later life health outcomes in offspring

Wiklund, Petri; Karhunen, Ville; Richmond, Rebecca C; Silva, Maneka De; Wielscher, Matthias; Rezwan, Faisal I.; Richardson, Tom G; Veijola, Juha; Heinz-Herzig, Karl; Holloway, John W.; Relton, Caroline; Sebért, Sylvain; Järvelin, Marjo‐Riitta

doi:10.1101/428896

Cited by 16 publications

(24 citation statements)

References 47 publications

(54 reference statements)

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“…In the current study, for the CpG sites that were affected by PSE, methylation levels were increased, which was seen at three time points in both sexes. Promoter methylation is usually associated with repressed gene expression, but recent findings [ 17 , 22 ] suggest that this association could also occur inversely, which is in line with our previous studies [ 29 , 30 ] and studies by others [ 35 ]. Interestingly, in three development stages, PSE caused a persistent increase of methylation at CpG-74 when compared to control groups.…”

Section: Discussionsupporting

confidence: 91%

“…Until now, many studies have described the adverse effects of smoking during pregnancy on foetal development [ 15 ], metabolic disease [ 16 , 17 ], smoking behaviour [ 18 , 19 ] and the risk to develop the smoking-related diseases such as chronic obstructive pulmonary disease (COPD) [ 20 ]. These observations are supported by experimental mouse studies from our own group [ 15 , 21 , 22 ] and others [ 23–25 ].…”

Section: Introductionmentioning

confidence: 99%

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Prenatal smoke exposure induces persistent Cyp2a5 methylation and increases nicotine metabolism in the liver of neonatal and adult male offspring

et al. 2020

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Prenatal smoke exposure (PSE) is a risk factor for nicotine dependence. One susceptibility gene for nicotine dependence is Cytochrome P450 (CYP) 2A6, an enzyme responsible for the conversion of nicotine to cotinine and nicotine clearance in the liver. Higher activity of the CYP2A6 enzyme is associated with nicotine dependence, but no research has addressed the PSE effects on the CYP2A6 gene or its mouse homologue Cyp2a5 . We hypothesized that PSE affects Cyp2a5 promoter methylation, Cyp2a5 mRNA levels, and nicotine metabolism in offspring. We used a smoke-exposed pregnant mouse model. RNA, DNA, and microsomal protein were isolated from liver tissue of foetal, neonatal, and adult offspring. Enzyme activity, Cyp2a5 mRNA levels, and Cyp2a5 methylation status of six CpG sites within the promoter region were analysed via HPLC, RT-PCR, and bisulphite pyrosequencing. Our data show that PSE induced higher cotinine levels in livers of male neonatal and adult offspring compared to controls. PSE-induced cotinine levels in neonates correlated with Cyp2a5 mRNA expression and promoter methylation at CpG-7 and CpG+45. PSE increased methylation in almost all CpG sites in foetal offspring, and this effect persisted at CpG-74 in male neonatal and adult offspring. Our results indicate that male offspring of mothers which were exposed to cigarette smoke during pregnancy have a higher hepatic nicotine metabolism, which could be regulated by DNA methylation. Given the detected persistence into adulthood, extrapolation to the human situation suggests that sons born from smoking mothers could be more susceptible to nicotine dependence later in life.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Prenatal smoke exposure induces persistent Cyp2a5 methylation and increases nicotine metabolism in the liver of neonatal and adult male offspring

et al. 2020

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“…Prenatal maternal smoking altered DNA methylation of a small group of genes. Effects persisted from birth into middle age for four genes that included the detoxifying enzymes CYP1A1 and AHRR, discussed in Phase II (1220 adults, prospective study of five birth cohorts; Wiklund et al 2019). Offspring of mice from mothers fed a fatty diet had increased histone methylation of the adipokine gene and reduced mRNA in adipose tissue; these effects persisted on normal diets into the F1 (next) generation, disappearing by F3 (Masuyama et al 2015).…”

Section: Epigenetics Of Pollutionmentioning

confidence: 99%

The Exposome in Human Evolution: From Dust to Diesel

Trumble¹,

Finch²

2019

The Quarterly Review of Biology

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Global exposures to air pollution and cigarette smoke are novel in human evolutionary history and are associated with about 16 million premature deaths per year. We investigate the history of the human exposome for relationships between novel environmental toxins and genetic changes during human evolution in six phases. Phase I: With increased walking on savannas, early human ancestors inhaled crustal dust, fecal aerosols, and spores; carrion scavenging introduced new infectious pathogens. Phase II: Domestic fire exposed early Homo to novel toxins from smoke and cooking. Phases III and IV: Neolithic to preindustrial Homo sapiens incurred infectious pathogens from domestic animals and dense communities with limited sanitation. Phase V: Industrialization introduced novel toxins from fossil fuels, industrial chemicals, and tobacco at the same time infectious pathogens were diminishing. Thereby, pathogen-driven causes of mortality were replaced by chronic diseases driven by sterile inflammogens, exogenous and endogenous. Phase VI: Considers future health during global warming with increased air pollution and infections. We hypothesize that adaptation to some ancient toxins persists in genetic variations associated with inflammation and longevity.

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“…aggression). This approach previously supported a causal effect of maternal smoking-associated methylation sites in blood on various traits and diseases for which well-powered GWASs have been performed, including schizophrenia 53,54 . For aggressive behavior, the currently available 55 largest GWASs of aggressive behavior included ~16,000 56 and ~75,000 participants (Ip et al, Multivariate GWA meta-analysis in over 500K observations on aggressive behavior and ADHD symptoms, submitted) , respectively.…”

Section: Discussionmentioning

confidence: 76%

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

Dongen

Hagenbeek

Suderman

et al. 2020

Preprint

Self Cite

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DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N=15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha=1.2×10−7; Bonferroni correction). In cord blood samples of 2,425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r=0.74, p=0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripherl blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range=3-82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

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DNA methylation links prenatal smoking exposure to later life health outcomes in offspring

Cited by 16 publications

References 47 publications

Prenatal smoke exposure induces persistent Cyp2a5 methylation and increases nicotine metabolism in the liver of neonatal and adult male offspring

Prenatal smoke exposure induces persistent Cyp2a5 methylation and increases nicotine metabolism in the liver of neonatal and adult male offspring

The Exposome in Human Evolution: From Dust to Diesel

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

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