DNA Methylation Signatures as Biomarkers of Prior Environmental Exposures
Purpose of Review
This review demonstrates the growing body of evidence connecting DNA methylation to prior exposure. It highlights the potential to use DNA methylation patterns as a feasible, stable, and accurate biomarker of past exposure, opening new opportunities for environmental and gene-environment interaction studies among existing banked samples.
We present the evidence for association between past exposure, including prenatal exposures, and DNA methylation measured at a later time in the life course. We demonstrate the potential utility of DNA methylation-based biomarkers of past exposure using results from multiple studies of smoking as an example. Multiple studies show the ability to accurately predict prenatal smoking exposure based on DNA methylation measured at birth, in childhood, and even adulthood. Separate sets of DNA methylation loci have been used to predict past personal smoking exposure (postnatal) as well. Further, it appears that these two types of exposures, prenatal and previous personal exposure, can be isolated from each other. There is also a suggestion that quantitative methylation scores may be useful for estimating dose. We highlight the remaining needs for rigor in methylation biomarker development including analytic challenges as well as the need for development across multiple developmental windows, multiple tissue types, and multiple ancestries.
If fully developed, DNA methylation-based biomarkers can dramatically shift our ability to carry out environmental and genetic-environmental epidemiology using existing biobanks, opening up unprecedented opportunities for environmental health.
KeywordsDNA methylation Biomarker Past exposure Environmental exposure Prenatal smoking EWAS Epigenomic
Compliance with Ethical Standards
Conflict of Interest
M. Daniele Fallin and Christine Ladd-Acosta each declare no potential conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 3.NTP monograph on health effects of low-level lead. NTP Monogr, 2012(1):xiii, xv-148.Google Scholar
- 26.• Joubert BR, et al. DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis. Am J Hum Genet. 2016;98(4):680–96 Largest epigenome-wide association study for prenatal smoking exposure to date, consisting of 6,685 samples from 13 studies. Identified thousands of loci showing DNA methylation changes in cord blood, at birth, related to in utero exposure to smoking.PubMedPubMedCentralCrossRefGoogle Scholar
- 31.•• Ladd-Acosta C, et al. Presence of an epigenetic signature of prenatal cigarette smoke exposure in childhood. Environ Res. 2016;144(Pt A):139–48 Reported prenatal smoking associated methylation patterns, originally detected in an independent birth sample, are also present in childhood. They were the first to report prenatal exposure to smoking can be accurately (AUC=0.87) predicted using DNA methylation patterns in the blood of 5 year old children.PubMedCrossRefPubMedCentralGoogle Scholar
- 32.• Richmond RC, et al. Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC). Hum Mol Genet. 2015;24(8):2201–17 Repeated biosampling in children, from birth to age 17, enabled examination of long-term persistence of prenatal smoking associated methylation changes in the same individuals over time. Significant differences in methylation were observed at multiple loci even after adjusting for postnatal household and personal exposures.PubMedCrossRefPubMedCentralGoogle Scholar
- 33.• Lee KW, et al. Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age. Environ Health Perspect. 2015;123(2):193–9 Shows DNA methylation changes related to prenatal exposure can be detected in adolescence. Also replicated findings in an independent sample at birth and ages 7 and 17.PubMedCrossRefPubMedCentralGoogle Scholar
- 40.Steegers-Theunissen RP, Obermann-Borst SA, Kremer D, Lindemans J, Siebel C, Steegers EA, et al. Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS One. 2009;4(11):e7845.PubMedPubMedCentralCrossRefGoogle Scholar
- 50.Finer S, Iqbal MS, Lowe R, Ogunkolade BW, Pervin S, Mathews C, et al. Is famine exposure during developmental life in rural Bangladesh associated with a metabolic and epigenetic signature in young adulthood? A historical cohort study. BMJ Open. 2016;6(11):e011768.PubMedPubMedCentralCrossRefGoogle Scholar
- 55.Sharp GC, Salas LA, Monnereau C, Allard C, Yousefi P, Everson TM, et al. Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium. Hum Mol Genet. 2017;26(20):4067–85.PubMedPubMedCentralCrossRefGoogle Scholar
- 57.•• Richmond RC, et al. DNA methylation as a marker for prenatal smoke exposure in adults. Int J Epidemiol. 2018; Showed methylation scores obtained from DNA collected at age 30, can predict prenatal exposure to smoking with 72% accuracy. Also showed loci associated with postnatal personal smoking are not good predictors of prenatal smoking exposure (AUC=0.57), suggesting methylation patterns differ by exposure window.Google Scholar
- 70.Knight AK, Conneely KN, Smith AK. Gestational age predicted by DNA methylation: potential clinical and research utility. Epigenomics. 2017.Google Scholar
- 76.•• Zhuang J, Widschwendter M, Teschendorff AE. A comparison of feature selection and classification methods in DNA methylation studies using the Illumina Infinium platform. BMC Bioinformatics. 2012;13:59 Developed a methylation score in cord blood at birth that reflects prenatal exposure to sustained smoking, The score was able to predict exposure status in an independent birth sample with 90% accuracy.PubMedPubMedCentralCrossRefGoogle Scholar
- 78.• Shenker NS, et al. DNA methylation as a long-term biomarker of exposure to tobacco smoke. Epidemiology. 2013;24(5):712–6 First to show generalized linear model, using methylation levels at 4 CpG sites, can accurately predict previous personal smoking history among adults.PubMedCrossRefPubMedCentralGoogle Scholar
- 83.Zhang GH, Lu Y, Ji BQ, Ren JC, Sun P, Ding S, et al. Do mutations in DNMT3A/3B affect global DNA hypomethylation among benzene-exposed workers in Southeast China?: effects of mutations in DNMT3A/3B on global DNA hypomethylation. Environ Mol Mutagen. 2017;58(9):678–87.PubMedCrossRefPubMedCentralGoogle Scholar
- 84.Declerck K, Remy S, Wohlfahrt-Veje C, Main KM, van Camp G, Schoeters G, et al. Interaction between prenatal pesticide exposure and a common polymorphism in the PON1 gene on DNA methylation in genes associated with cardio-metabolic disease risk-an exploratory study. Clin Epigenetics. 2017;9:35.PubMedPubMedCentralCrossRefGoogle Scholar