Gaps in Knowledge and Missing Evidence in the Role of DNA Methylation in Biological Embedding
The thrifty phenotype hypothesis – the theory that under- or malnutrition during gestation could permanently influence the body’s structure and function contributing to adult disease – has then been closely linked with biological embedding, the process through which external exposures “get under the skin” to influence human biological processes.
Biological embedding has been hypothesized to occur through three different processes which may often coexist: latent effects, cumulative effects, and pathway effects. Irrespective of the exact mechanism, in order for biological embedding to occur, responses to an environmental signal need to be stage dependent, heritable, and persistent. Such phenotypic effects can be explained by epigenetic modifications imposed by environmental signals, which are themselves heritable, time dependent, and tissue as well as sex specific. DNA methylation is the epigenetic mechanism that has been most extensively studied in this context.
The synthesis of current research relating to the biological embodiment of early-life exposures through DNA methylation provides some support to the involvement of DNA methylation in biological embedding and provides evidence for a mechanism through which early-life exposures can affect disease risk later in life.
However, there still remain several gaps in knowledge which are discussed in this chapter. In order to generate evidence that will strongly support and further elucidate the role of DNA methylation in biological embedding of early-life exposures, these gaps need to be addressed in more and better designed studies.
KeywordsBiological embedding Thrifty phenotype hypothesis Developmental plasticity DNA methylation Epigenetics Exposome Early-life nutrition Early-life socioeconomic status Childhood obesity Childhood overweight Chronic disease
List of Abbreviations
5′—C—phosphate—G—3′, cytosine and guanine separated by only one phosphate
Insulin-like growth factor-2
- Bellavia A, Urch B, Speck M, Brook RD, Scott JA, Albetti B, Behbod B et al (2013) DNA hypomethylation, ambient particulate matter, and increased Blood pressure: findings from controlled human exposure experiments. J Am Heart Assoc 2(3):e000212. https://doi.org/10.1161/JAHA.113.000212CrossRefPubMedPubMedCentralGoogle Scholar
- Christensen BC, Andres Houseman E, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL, Nelson HH et al (2009) Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 5(8):e1000602. https://doi.org/10.1371/journal.pgen.1000602CrossRefPubMedPubMedCentralGoogle Scholar
- Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN, Issa JP, Sidransky D, Baylin SB, Herman JG (2000) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to a mutations in K-Ras in colorectal tumorigenesis. Cancer Res 60(9):2368–2371PubMedGoogle Scholar
- Fasanelli F, Baglietto L, Ponzi E, Guida F, Campanella G, Johansson M, Grankvist K et al (2015) Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts. Nat Commun 6:10192. https://doi.org/10.1038/ncomms10192CrossRefPubMedPubMedCentralGoogle Scholar
- Gluckman PD, Hanson MA (2004) Developmental origins of disease paradigm: a mechanistic and evolutionary perspective. Pediatr Res 56(3):311–317. https://doi.org/10.1203/01.PDR.0000135998.08025.FBCrossRefPubMedGoogle Scholar
- Gluckman PD, Hanson MA (2008) Mismatch: the lifestyle diseases timebomb. Oxford University Press, OxfordGoogle Scholar
- Gluckman PD, Hanson MA, Spencer HG, Bateson P (2005) Environmental influences during development and their later consequences for health and disease: Implications for the interpretation of empirical studies. Proc R Soc B Biol Sci 272(1564):671–677. https://doi.org/10.1098/rspb.2004.3001CrossRefGoogle Scholar
- Herceg Z, Lambert M-P, van Veldhoven K, Demetriou C, Vineis P, Smith MT, Straif K, Wild CP (2013) Towards incorporating epigenetic mechanisms into carcinogen identification and evaluation. Carcinogenesis. https://doi.org/10.1093/carcin/bgt212
- Howe LD, Smith AD, Macdonald-Wallis C, Anderson EL, Galobardes B, Lawlor DA, Ben-Shlomo Y et al (2016) Relationship between mediation analysis and the structured life course approach. Int J Epidemiol. https://doi.org/10.1093/ije/dyw254
- Relton CL, Smith GD (2010) Epigenetic epidemiology of common complex disease: prospects for prediction, prevention, and treatment. PLoS Med 7(10). https://doi.org/10.1371/journal.pmed.1000356
- Simpkin AJ, Suderman M, Gaunt TR, Lyttleton O, McArdle WL, Ring SM, Tilling K, Smith GD, Relton CL (2015) Longitudinal analysis of DNA methylation associated with birth weight and gestational age. Hum Mol Genet 24(13):3752–3763. https://doi.org/10.1093/hmg/ddv119CrossRefPubMedPubMedCentralGoogle Scholar
- Tobi EW, Lumey LH, Talens RP, Kremer D, Putter H, Stein AD, Eline Slagboom P, Heijmans BT (2009) DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 18(21):4046–4053. https://doi.org/10.1093/hmg/ddp353CrossRefPubMedPubMedCentralGoogle Scholar
- Wild CP (2012) The exposome: from concept to utility. Int J Epidemiol. https://doi.org/10.1093/ije/dyr236