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Epigenetics and DOHaD: how translation to predictive testing will require a better public understanding

Published online by Cambridge University Press:  18 October 2021

Fiona Lynch
Affiliation:
Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
Sharon Lewis
Affiliation:
Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
Ivan Macciocca
Affiliation:
Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia Victorian Clinical Genetics Services, Parkville, Victoria, Australia
Jeffrey M. Craig*
Affiliation:
Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, Victoria, Australia
*
Address for correspondence: Jeffrey M. Craig, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia. Email: jeffrey.craig@deakin.edu.au
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Abstract

Epigenetics is likely to play a role in the mediation of the effects of genes and environment in risk for many non-communicable diseases (NCDs). The Developmental Origins of Health and Disease (DOHaD) theory presents unique opportunities regarding the possibility of early life interventions to alter the epigenetic makeup of an individual, thereby modifying their risk for a variety of NCDs. While it is important to determine how we can lower the risk of these NCDs, it is equally important to understand how the public’s knowledge and opinion of DOHaD and epigenetic concepts may influence their willingness to undertake such interventions for themselves and their children. In this review, we provide an overview of epigenetics, DOHaD, NCDs, and the links between them. We explore the issues surrounding using epigenetics to identify those at increased risk of NCDs, including the concept of predictive testing of children. We also outline what is currently understood about the public’s understanding and opinion of epigenetics, DOHaD, and their relation to NCDs. In doing so, we demonstrate that it is essential that future research explores the public’s awareness and understanding of epigenetics and epigenetic concepts. This will provide much-needed information which will prepare health professionals for the introduction of epigenetic testing into future healthcare.

Type
Review
Copyright
© The Author(s), 2021. Published by Cambridge University Press in association with International Society for Developmental Origins of Health and Disease

Introduction

Epigenetics describes the study of molecules and mechanisms that can perpetuate alternative gene activity states in the context of the same DNA sequence. Reference Cavalli and Heard1 Epigenetic state is influenced by genes, environment and development. Current evidence implicates epigenetic mechanisms in mediating risk for many non-communicable diseases (NCDs): chronic, non-infectious conditions which collectively contribute to an increasing burden on the healthcare system as their prevalence increases. The Developmental Origins of Health and Disease (DOHaD) theory presents unique opportunities regarding the possibility of early life interventions to alter the epigenetic makeup of an individual, thereby modifying their risk for a variety of NCDs. Reference Cavalli and Heard1 While it is important to determine how we can reduce the risk of NCDs, it is equally important to understand how the public’s knowledge and opinion of DOHaD and epigenetic concepts may influence their willingness to undertake interventions for themselves and their children to prevent NCDs.

In this narrative review, we provide an overview of epigenetics, DOHaD, NCDs, and the links between them. We explore the issues surrounding the use of epigenetic testing to identify children and adults at increased risk of NCDs. We also outline what is currently understood about the public’s understanding and opinion of concepts related to epigenetics and DOHaD, and their relationship with NCDs. In doing this, we demonstrate that it is essential that future research explores the public’s views and understanding of epigenetics and epigenetic concepts, providing much needed information which will prepare the public and health professionals for the introduction of epigenetic testing into healthcare in the future.

Search strategy

Publications for this literature review were obtained through searches of the Medline and Embase databases, as well as Google Scholar and Discovery at the University of Melbourne, using combinations of the following and related search terms: ‘epigenetics’, ‘genetics’, ‘attitudes to health’, ‘DOHaD’, ‘parents’, ‘opinions’, and ‘chronic health’.

Epigenetics

It is currently widely accepted that the developmental trajectory of an individual is not simply a competition between two opposing factors (nature and nurture), but rather represents a complex interaction between genetic and environmental factors. Reference Morris, Gwinn, Clyne and Khoury2-Reference Dupras and Ravitsky4 Genetic (nature) and environmental (nurture) factors do not act independently of each other during development. Reference Morris, Gwinn, Clyne and Khoury2 Instead, they interact in a number of different ways, one of these being through epigenetic mechanisms. Furthermore, this gene-environment interaction can change and evolve throughout a person’s life, Reference Weaver3 suggesting that it is not only the initial developmental stages of life which influence an individual’s health and risk of disease. Epigenetics has provided the means for a paradigm shift in the nature versus nurture debate. Reference Lappé5

Conrad Waddington was the first to define epigenetics as ‘the interactions of genes with their environment, which bring the phenotype into being’ (p.298). Reference Dolinoy, Weidman and Jirtle6 His idea was supported by the discovery of a potential underlying mechanism of epigenetic action, DNA methylation, in the 1970s by Holliday and Pugh. Reference Dolinoy, Weidman and Jirtle6 The word ‘epigenetics’ has historically been ambiguous; its definition has changed dramatically over time as the science behind it has progressed. Reference Greally7 Today, however, the term ‘epigenetics’ is generally used to describe more specifically modifications to DNA and gene expression that do not involve changes to the DNA sequence itself, Reference Dolinoy, Weidman and Jirtle6-Reference Richardson, Daniels and Gillman10 or alternatively, ‘experience-dependent molecular alterations to DNA or to proteins that alter how genes behave without changing the information they contain’ (p.171). Reference Nestler11

Epigenetics plays a major role in mammals in phenomena such as genomic imprinting (where parent-of-origin epigenetic markers determine gene expression) and X-inactivation (the epigenetic process by which one X chromosome is deactivated in females). Reference Dolinoy, Weidman and Jirtle6 Epigenetic markers (such as DNA methylation, histone modification, and DNA packaging) are involved in the regulation and expression of genes, both spatially (across different tissue types) and temporally (across developmental stages). Reference Dolinoy, Weidman and Jirtle6,Reference Rothstein, Cai and Marchant8 Epigenetic markers control gene expression by affecting when and how genes are expressed. Reference Rothstein, Cai and Marchant8 Epigenetic markers are unique compared to DNA sequence for a number of reasons, including their susceptibility to influence by the environment. Reference Rothstein, Cai and Marchant8 It is also plausible that in some cases, they may be transmissible from parent to offspring. Reference Dolinoy, Weidman and Jirtle6 In order to understand the influence that the environment has on epigenetic markers, and their potential inheritance, it is important to first understand the process of epigenetic reprogramming.

Epigenetic reprogramming

Epigenetic reprogramming occurs at several time points during development, including gametogenesis (when eggs and sperm are created) and in early embryogenesis Reference Dolinoy, Weidman and Jirtle6,Reference Vanhees, Vonhogen, van Schooten and Godschalk12 (Fig. 1). Epigenetic reprogramming involves genome-wide ‘resetting’ of epigenetic markers, Reference Dolinoy, Weidman and Jirtle6 the best understood of which is DNA methylation. Global demethylation is thought to occur in order to restore totipotency to the cell; however, some areas of the genome are protected from this global demethylation, such as imprinted genes. Reference Dolinoy, Weidman and Jirtle6,Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13 Epigenetic markers within these regions are known as ‘parent-of-origin methylation marks’ (p.272) Reference Vanhees, Vonhogen, van Schooten and Godschalk12 and are essential for the correct expression of these genes. De novo methylation of the genome then occurs around the time of implantation, which coincides with the first cell lineage determination stage Reference Dolinoy, Weidman and Jirtle6,Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13 and establishes a new pattern of DNA methylation in the blastocyst. Reference Vanhees, Vonhogen, van Schooten and Godschalk12 There are currently around 100 known imprinted genes; however, a growing consensus suggests there are likely other genes that also elude reprogramming through similar mechanisms. Reference Hughes14 This is the basis of intergenerational epigenetic inheritance. Reference Rothstein, Cai and Marchant8,Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13 Because of this global demethylation and subsequent de novo methylation process, there are several time points at which the epigenome is most sensitive to disruptors, namely during gestation, neonatal development, adolescence, and late adulthood. However, the epigenome is at its most vulnerable during embryogenesis, Reference Dolinoy, Weidman and Jirtle6 gestation and newborn stages Reference Rothstein, Cai and Marchant8 due to high rates of cell division at these times. Furthermore, changes to epigenetic state can be sensitive and specific to the developmental stage at which they occur. Reference Rothstein, Cai and Marchant8

Fig. 1. Alterations in DNA methylation status during cell development. Reused with permission from Jirtle and Skinner Reference Jirtle and Skinner16 . Global demethylation (and therefore epigenetic reprogramming) occurs at two key time points during development, during gametogenesis and early embryogenesis.

Although intergenerational epigenetic inheritance has been observed in mammals, Reference Dolinoy, Weidman and Jirtle6,Reference Hughes14 the mechanism by which it occurs remains elusive. Reference Gluckman, Hanson and Beedle15,Reference Jirtle and Skinner16 Knowledge of mitotic inheritance of epigenetic markers is well established; however, the global demethylation and reprogramming which occurs during gametogenesis and after conception poses a challenge for understanding the intergenerational inheritance of epigenetic markers. Reference Gluckman, Hanson and Beedle15 It should be remembered that although the following concepts are described mostly in terms of intrauterine environment, both maternal and paternal effects have been observed in transgenerational epigenetic inheritance, Reference Richardson, Daniels and Gillman10,Reference Vanhees, Vonhogen, van Schooten and Godschalk12 hence, ‘the paternal influence on epigenetic alterations in offspring should not be neglected’ (p.274). Reference Vanhees, Vonhogen, van Schooten and Godschalk12

Epigenetic exceptionalism

While there is much research focusing on the ethical issues of genetic concepts and genetic inheritance, there has been argument as to whether, ethically, epigenetics should be considered any differently. Reference Rothstein, Cai and Marchant8,Reference Rothstein17 From a scientific point of view, it is clear that the two have both similarities and differences. The most obvious difference between genetics and epigenetics is that, unlike genetic changes, epigenetic changes can be reversible. Reference Rothstein, Cai and Marchant8 Possibly less known is the fact that epigenetic changes occur more frequently than DNA mutations. Reference Rothstein, Cai and Marchant8 Furthermore, unlike genetic mutations, excluding the mechanism of mutagenesis, epigenetic markers may be influenced by the environment. Reference Rothstein, Cai and Marchant8,Reference Chadwick and O’Connor18 A similarity between genetics and epigenetics is that epigenetic changes may also be inherited. Reference Rothstein, Cai and Marchant8 Some have suggested that, despite its differences, epigenetics poses the same ethical issues as genetics, albeit potentially more complex. Reference Rothstein, Cai and Marchant8,Reference Chadwick and O’Connor18 However, because epigenetic variants can be reversible, and therefore more easily prevented or treated, responsibility on parents and societal blame for children’s epigenetic conditions could be greater than that for genetic conditions. Reference Dupras and Ravitsky4

Developmental plasticity and developmental mismatch

Developmental plasticity, sometimes referred to as phenotypic plasticity, Reference Weaver3 biological embedding, Reference Moore, Arefadib, Deery and Sue West19 or fetal programming Reference Lumey, van Poppel, Lumey and Vaiserman20 is the process whereby a fetus ‘utilizes environmental cues to adjust individual phenotype to the current and predicted environment’ (p.8). Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13 This allows the fetus to use information about the current environment as a ‘weather forecast’ for the future environment, and to develop and adapt accordingly. Reference Moore, Arefadib, Deery and Sue West19 The process of developmental plasticity not only explains how one genotype can produce a range of phenotypes, Reference Dolinoy, Weidman and Jirtle6,Reference Jablonka and Lamb21 but it also provides an evolutionary advantage. This is because developmental plasticity allows the fetus to become best adapted to the predicted environment by adjusting its phenotype to best match environmental demand. Reference Weaver3 Developmental plasticity is therefore thought to help an individual more quickly adapt to their environment, bypassing the long process of genetic evolution. Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13,Reference Barker22

Because of developmental plasticity, the environmental factors acting during an individual’s early life set the trajectory for their developmental course, moulding the phenotype to those specific environmental inputs. Reference Bay, Mora, Sloboda, Morton, Vickers and Gluckman23 It has therefore been suggested that the early life environment can affect the phenotype permanently and into adult life. Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13 At the molecular level, the concept of developmental plasticity describes an individual’s ability to ‘tune’ gene expression Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13 through a ‘weather forecast’ Reference Barker22 from the mother. This tuning can be achieved via epigenetic mechanisms. Epigenetic programming is therefore proposed as a mechanism for developmental plasticity, Reference Weaver3,Reference Dupras and Ravitsky4,Reference Dolinoy, Weidman and Jirtle6,Reference Vanhees, Vonhogen, van Schooten and Godschalk12 as it affects regulation of gene expression, and is both influenced by early life environment, and consistent into adult life. Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13

Although epigenetics may have conferred a selective advantage throughout evolutionary history, today it instead exacerbates disease risk across generations. Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13 The reason for this can be explained through the ‘developmental mismatch’ theory, where the future environment does not reflect that which was predicted, resulting in the individual being at increased risk of disease. Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13 Although such adaptations may be beneficial in the short term, they may cause disease in the long term if the environment changes. Reference Lumey, van Poppel, Lumey and Vaiserman20 Such dramatic changes in predicted and actual environment can result from circumstances such as inaccurate environmental cues during gestation, Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13 or dramatic shifts in nutrition due to improved socio-economic status. Godfrey et al. Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13 also suggest that the degree of mismatch between the predicted and actual environment is directly related to the risk of disease. This is particularly relevant for societies undergoing rapid economic growth, Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13 where one generation may experience a far richer environment than previous generations.

The developmental mismatch concept was shown most notably in a study conducted by Roseboom et al., Reference Roseboom, van der Meulen, Ravelli, Osmond, Barker and Bleker24 who examined individuals who had been exposed to extreme famine in the Netherlands during World War II. Because the Dutch famine occurred over a short period of time (only a few months), records were kept immaculately, and the population were well-nourished both before and after the famine, this particular occurrence provided a unique opportunity to study the effects of undernutrition on pregnant women and their resulting children. Reference Lumey, van Poppel, Lumey and Vaiserman20,Reference Roseboom, van der Meulen, Ravelli, Osmond, Barker and Bleker24 The study revealed that the undernutrition of mothers during pregnancy affected a child’s health in later life, Reference Roseboom, van der Meulen, Ravelli, Osmond, Barker and Bleker24 and that the effect directly depended on both the timing during gestation at which the famine was experienced and on the specific systems under embryonic and fetal development at that time. Reference Roseboom, van der Meulen, Ravelli, Osmond, Barker and Bleker24 Outcomes such as adult body size, diabetes, and schizophrenia showed the most association with prenatal exposure to famine. Reference Lumey, van Poppel, Lumey and Vaiserman20 Epigenetic changes also showed an association with prenatal famine, providing a possible mechanism for the adult disease outcomes. Reference Lumey, van Poppel, Lumey and Vaiserman20

Developmental Origins of Health and Disease

A major implication of the developmental plasticity and developmental mismatch concepts is the overarching DOHaD theory. Reference Bay, Mora, Sloboda, Morton, Vickers and Gluckman23 Sometimes referred to as the ‘fetal basis of adult disease’ or the ‘early origins’ theory, the DOHaD theory suggests that ‘nutrition and other environmental factors during prenatal and early postnatal development influence developmental plasticity, thereby altering susceptibility to adult chronic diseases’ (p.298). Reference Dolinoy, Weidman and Jirtle6 In addition, the First 1000 Days concept builds on the DOHaD theory by suggesting that the first 1000 days of development (from conception until age two) are the most crucial in affecting future disease risk. Reference Mameli, Mazzantini and Zuccotti25 The concept of the First 1000 Days has been described in the literature based on recent evidence emphasising the importance of this early life stage. Reference Moore, Arefadib, Deery and Sue West19,Reference Mameli, Mazzantini and Zuccotti25

Because of its implication in many common diseases, it is well accepted that the DOHaD concept has worldwide public health implications, Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13 as the fetal environment impacts the developmental trajectory, and therefore disease risk, of every child across the globe. Reference Bay, Mora, Sloboda, Morton, Vickers and Gluckman23 Additionally, environmental factors can affect multiple future generations through the inheritance of epigenetic markers, despite their continued lack of exposure to such factors, Reference Dolinoy, Weidman and Jirtle6 further emphasising the importance of epigenetic concepts in global health strategy. Despite this recognised importance, translation of DOHaD knowledge into public health policy and guidelines has been limited. Reference Jacob and Hanson26

Epigenetics and NCD

Evidence suggests that epigenetics plays a significant role in disease susceptibility in adult life. Reference Dolinoy, Weidman and Jirtle6 Changes in epigenetic regulation are associated with an increasing number of diseases, including but not limited to: type 2 diabetes, Reference Lappé5,Reference Vanhees, Vonhogen, van Schooten and Godschalk12,Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13,Reference Jirtle and Skinner16 cancer, Reference Lappé5,Reference Dolinoy, Weidman and Jirtle6,Reference Vanhees, Vonhogen, van Schooten and Godschalk12,Reference Jirtle and Skinner16 cardiovascular disease, Reference Lappé5,Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13,Reference Jirtle and Skinner16 obesity, Reference Lappé5,Reference Vanhees, Vonhogen, van Schooten and Godschalk12,Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13,Reference Jirtle and Skinner16,Reference Chadwick and O’Connor18,Reference Mameli, Mazzantini and Zuccotti25 and mental illness, Reference Lappé5,Reference Dolinoy, Weidman and Jirtle6,Reference Scott9,Reference Jirtle and Skinner16 suggesting that the range of epigenetic influence across all aspects of human health is vast. There is widespread agreement that epigenetics plays a significant role in human health, Reference Egger, Liang, Aparicio and Jones27-Reference Peedicayil29 and new evidence is emerging regularly linking epigenetic changes to increasingly more aspects of human disease. Reference Peedicayil29

Also known as chronic diseases, NCDs are non-infectious, long-lasting conditions which are caused by a combination of genetic and environmental factors. 30 They include cardiovascular disease, cancer, chronic respiratory disease, and diabetes. 30 The prevalence of NCDs across the globe is increasing, Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13,Reference Barker, Barker, Fleming and Lampl31 generating a significant burden on global economies and worldwide health. Reference Bay, Mora, Sloboda, Morton, Vickers and Gluckman23 As of 2014, NCDs were more common worldwide than communicable diseases, a statistic which is likely only to worsen. Reference Hanson, Gluckman, Godfrey, Seckl and Christen32 Particularly in Western countries, where they present one of the major health problems, Reference Roseboom, van der Meulen, Ravelli, Osmond, Barker and Bleker24 NCDs are the modern-day epidemic. Reference Gluckman, Hanson and Low33 For example, the global prevalence of type 2 diabetes is expected to double by the year 2030, and the prevalence of cardiovascular disease is expected to increase by 35%. Reference Barker, Barker, Fleming and Lampl31 NCDs cause 41 million deaths worldwide each year, contributing to 71% of global mortality, and accounting for over 80% of premature mortality. Reference Riley, Guthold and Cowan34 Furthermore, 85% of these premature deaths occur in low- and middle-income countries, Reference Riley, Guthold and Cowan34 indicating the impact of social and economic deprivation on these diseases. There is a significant amount of evidence to suggest that environmental factors acting during the early stages of life are contributing to this rising epidemic. Reference Barker, Barker, Fleming and Lampl31 Therefore, because the majority of these deaths are preventable, Reference Riley, Guthold and Cowan34 there is an important need for appropriate interventions.

Predictive epigenetic testing

Some have suggested that early identification of those at increased risk of NCDs may help encourage individuals to undertake preventative measures. Reference Hanson, Gluckman, Godfrey, Seckl and Christen32 Epigenetics provides new opportunities for biomarkers which identify those at increased risk of NCDs. Reference Hanson, Gluckman, Godfrey, Seckl and Christen32,Reference Hanson and Gluckman35,Reference Park and Kobor36 In fact, potential epigenetic biomarkers predictive of future disease are already being discovered. Reference Sharp and Relton37 For example, Murray Reference Murray, Bryant and Titcombe38 showed that DNA methylation state at birth is predictive of cardiovascular disease in late childhood. Research has also shown that DNA methylation is also associated with prenatal alcohol consumption and tobacco use. Reference Sharp and Relton37 Furthermore, advances in the field of cancer include the adoption of DNA methylation screening to help predict the efficacy of certain drugs. Reference Heyn, Méndez-González and Esteller39 Of course, these kinds of discoveries require not only labour-intensive research, but often time-intensive longitudinal studies in order to determine causality, rather than simply correlation. Reference Sharp and Relton37 However, these epigenetic biomarkers allow for predictive epigenetic testing for an increasing number of health conditions. This will have many benefits, including the opportunity to further the prospect of personalised medicine in everyday health care by targeting those individuals who are at an increased risk, and providing early interventions to mitigate that risk. Reference Chadwick and O’Connor18,Reference Peedicayil29 In particular, inroads into personalised medicine will provide opportunities for therapies targeted to the individual’s epigenome. Reference Heyn, Méndez-González and Esteller39,Reference Weber40 Godfrey et al. Reference Godfrey, Lillycrop, Burdge, Gluckman and Hanson13 suggest that continuing research into epigenetic mechanisms will allow development of potential interventions. The reversibility of epigenetic markers provides a particularly promising opportunity for treatment and prevention of epigenetic disease, Reference Rothstein, Cai and Marchant8,Reference Egger, Liang, Aparicio and Jones27,Reference Hanson, Gluckman, Godfrey, Seckl and Christen32 resulting in a push for the advent of new epigenetic therapies. Reference Egger, Liang, Aparicio and Jones27

While predictive epigenetic testing may provide information to inform early intervention, Reference Hanson, Gluckman, Godfrey, Seckl and Christen32 it may not necessarily lead to positive behaviour change. The Health Belief Model suggests that there are multiple factors which influence people’s health behaviours, including their perceived risk of disease. Reference Fang, Dunkel-Schetter and Tatsugawa41,Reference Rosenstock42 Risk perception is therefore an important consideration in assessing the personal and clinical utility of both testing and public health messaging, however there is limited research in this area in the context of epigenetic testing.

Public understanding and opinion of epigenetics

While there has been some research in exploring the public’s understanding of genetic and environmental susceptibility to disease, in line with the ‘nature versus nurture’ debate, Reference Morris, Gwinn, Clyne and Khoury2,Reference Condit43 research in this area is lacking. Some suggest that the public views genetic factors as contributing only a small role to human disease and associated with only diseases which are viewed as severe or incurable. Reference Morris, Gwinn, Clyne and Khoury2 This is contrary to other literature showing genetic susceptibility plays a role in a significant portion of human diseases which are generally considered to be caused by environmental factors, such as lung cancer caused by cigarette smoking, pesticide and lead toxicity, infectious diseases and the effects of certain drugs. In fact, the ‘gene-environment interaction is fundamental to nearly all diseases’ (p.27). Reference Morris, Gwinn, Clyne and Khoury2 Despite this, the majority of people understand that both genetic and environmental factors contribute to an individual’s overall health; however, people tend to treat these as discrete factors without interaction. Reference Condit43 This is contradictory to what epigenetic research suggests. Condit showed that the public tend to view genetics ‘through the lens of heredity’ (p.1) Reference Condit43 rather than by understanding the underpinning biological mechanisms by which inheritance operates. While there is limited data about the public’s awareness and understanding of epigenetic concepts, epigenetics is highly prevalent throughout mainstream media, creating potential for widespread misconception and over-hype. Reference Dubois, Louvel, Le Goff, Guaspare and Allard44 Ultimately, studies show that the public’s understanding of common disease genetics is low, Reference Tercyak, Hensley Alford and Emmons45,Reference Smerecnik, Mesters, de Vries and de Vries46 suggesting that their knowledge of epigenetics is likely to be even more limited.

Testing in childhood

Because predictive epigenetic testing is likely to occur in early childhood in order for early interventions to be most effective, ethical issues arise which are similar to those relating to predictive genetic testing in children. There has been much professional discussion surrounding the ethical appropriateness of genetic testing in children. Reference Fallat, Katz and Mercurio47 There has also been some research exploring parents’ views of this issue Reference Tercyak, Hensley Alford and Emmons45,Reference Campbell and Ross48-Reference Shkedi-Rafid, Fenwick, Dheensa and Lucassen50 ; however, some have suggested that this research is insufficient to fully explore the attitudes of parents and health professionals towards the genetic testing of children. Reference Segal, Polansky and Sankar49 The vast majority of consensus statements advise against genetic testing in children for adult-onset conditions for which there are no effective preventative measures available in childhood Reference Fallat, Katz and Mercurio47,Reference Campbell and Ross48 ; however this is often in opposition to parents’ views. Campbell and Ross Reference Campbell and Ross48 suggest that the views of parents vary greatly with regard to wanting to know their children’s genetic predispositions to adult conditions. Almost half of the sample surveyed by Shkedi-Rafid et al. Reference Shkedi-Rafid, Fenwick, Dheensa and Lucassen50 were of the opinion that parents should be able to test their children for adult-onset conditions, even when there was no treatment or preventative measures available. Similarly, a study led by Tarini found that greater than one-third of parents expressed interest in predictive genetic testing for their children for untreatable adult-onset diseases. Reference Tarini, Singer, Clark and Davis51 Tercyak et al. Reference Tercyak, Hensley Alford and Emmons45 showed that parents saw the benefits of genetic testing in childhood to outweigh the risks. These benefits included the knowledge of the predisposition itself, and the associated preparedness that this knowledge provided, both emotionally and practically. Reference Tercyak, Hensley Alford and Emmons45,Reference Shkedi-Rafid, Fenwick, Dheensa and Lucassen50 This may be in part due to the assumption of parents that although there were no known effective interventions, they may still be able to utilise the information (such as changing their child’s diet or being more open to new treatments when they become available). Reference Shkedi-Rafid, Fenwick, Dheensa and Lucassen50

Anticipating parents’ questions, reactions, and general knowledge about genetic testing is important in order to provide the best healthcare possible, and to facilitate effective informed decision making Reference Tercyak, Hensley Alford and Emmons45,Reference Shkedi-Rafid, Fenwick, Dheensa and Lucassen50 by educating health professionals as to the motivations behind parents’ requests. Reference Tarini, Singer, Clark and Davis51 Further research into this area may allow the discrepancies between public and professional opinion to become clearer, and the reasons behind such discrepancies to be addressed. Reference Shkedi-Rafid, Fenwick, Dheensa and Lucassen50 As summarised by Etchegary et al., ‘optimal utilisation of any genetic testing depends on the knowledge and attitudes of the potential consumers of genetic tests and technologies’ (p.354). Reference Etchegary, Dicks, Green, Hodgkinson, Pullman and Parfrey52 This will likely also be the case with epigenetic testing, by allowing health professionals to be better prepared for the implementation of such testing in childhood. However, ethical issues surrounding the use of predictive testing for children, as well as equity and access of testing, will need to be considered as epigenetic testing is adopted.

How knowledge of DOHaD concepts can improve health outcomes

While there have been limited attempts at knowledge translation of DOHaD concepts beyond the scientific community, Reference McKerracher, Moffat, Barker, Williams and Sloboda53 early research suggests that educational interventions can influence health outcomes. Reference Bay, Mora, Sloboda, Morton, Vickers and Gluckman23,Reference Bay, Vickers, Mora, Sloboda and Morton54 An example which is relevant in the context of epigenetics is a study from Bay et al., Reference Bay, Mora, Sloboda, Morton, Vickers and Gluckman23,Reference Bay, Vickers, Mora, Sloboda and Morton54 where adolescents’ knowledge of DOHaD concepts before and after an in-school educational intervention were examined, and it was found that both knowledge and health outcomes were improved immediately following the intervention, Reference Bay, Mora, Sloboda, Morton, Vickers and Gluckman23 and at 12 months’ post-intervention. Reference Bay, Vickers, Mora, Sloboda and Morton54 The participants showed increased positive lifestyle and nutritional behaviours as well as a better understanding of the long-term and intergenerational impact of these behaviours. Reference Bay, Mora, Sloboda, Morton, Vickers and Gluckman23 The overall conclusion suggested that these types of interventions may be more effective in early life, in comparison to more traditional mid-life changes, Reference Bay, Mora, Sloboda, Morton, Vickers and Gluckman23 providing better health as well as economic outcomes. This increased knowledge also has the potential to be passed down to future generations, providing further benefit to the extended family. Reference Bay, Mora, Sloboda, Morton, Vickers and Gluckman23

For the evidence supporting DOHaD to benefit society as a whole, it must be understood by the public so they can make decisions about its use. Reference Bay and Vickers55 Therefore, educational interventions such as the one used by Bay et al. Reference Bay, Mora, Sloboda, Morton, Vickers and Gluckman23 are likely to be an important step in the prevention of NCDs. These types of interventions have been suggested at the prenatal stage, Reference Barker, Barker, Fleming and Lampl31,Reference Hanson and Gluckman35 during childhood, Reference Bateson, Barker and Clutton-Brock56 or during adolescence. Reference Hanson, Gluckman, Godfrey, Seckl and Christen32,Reference Bay and Vickers55 Alternatively, before and during pregnancy would be an optimal time to target women, as it is at this stage that they are most receptive to health advice for their future children. Reference Roseboom, van der Meulen, Ravelli, Osmond, Barker and Bleker24 Others have recommended that addressing the challenge of NCDs will require a life-course approach, with interventions targeted at many life stages. Reference Hanson and Gluckman35 Limited research into the knowledge translation of DOHaD concepts also points to the recommendation that interventions should be aimed at multiple generations simultaneously. Reference McKerracher, Moffat, Barker, Williams and Sloboda53

While increased knowledge is likely to lead to improved overall health outcomes, Reference Bay, Mora, Sloboda, Morton, Vickers and Gluckman23 it is also important that we do not forget the large impact of socio-economic factors on NCD disease risk. 30 Being impoverished greatly increases an individual’s risk of NCDs due to increased exposure to environmental factors such as tobacco use and poor diet. 30 Educational interventions that shed light on human behaviour and its impact on transgenerational epigenetic inheritance should be careful not to place blame and increase stigma on communities – and particularly mothers within these communities – affected by such socio-economic factors. Additionally, improved public awareness and understanding of epigenetics and DOHaD concepts should be just one intervention in a suite of public health initiatives designed to combat the increasing prevalence of NCDs globally, with a focus on disadvantaged populations with potentially less control over environmental factors impacting the health of future generations.

Conclusion

Research today is only beginning to delve into the possible consequences of epigenetic states in predicting disease risk with evidence currently too preliminary to provide recommendations for interventions. There is still much to be learnt about epigenetics and the DOHaD theory, and their respective effects on human health. Reference Holliday57 However, epigenetics is currently one of the most rapid growing fields of biology Reference Weber40 ; ‘epigenetics is in vogue’, Reference Nestler11 suggesting that it will not be long before epigenetic links between environment and disease are numerous and replicated, and epigenetic testing becomes easily accessible to the average consumer. In preparation for such a time, we must better grasp the public’s awareness and understanding of epigenetics, DOHaD, and their link to NCDs. This will better ready the health system to tackle this novel form of risk information which is likely to be generated from epigenetic testing.

Acknowledgements

This literature review was adapted from a previous version completed in partial fulfilment of the requirements for the Master of Genetic Counselling, University of Melbourne, Victoria, Australia.

Financial Support

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

Conflicts of Interest

The authors declare no potential conflict of interest.

References

Cavalli, G, Heard, E. Advances in epigenetics link genetics to the environment and disease. Nature. 2019; 571(7766), 489499.CrossRefGoogle Scholar
Morris, J, Gwinn, M, Clyne, M, Khoury, MJ. Public knowledge regarding the role of genetic susceptibility to environmentally induced health conditions. Community Genet. 2003; 6(1), 2228.Google ScholarPubMed
Weaver, IC. Epigenetic programming by maternal behavior and pharmacological intervention. Nature versus nurture: let’s call the whole thing off. Epigenetics. 2007; 2, 2228.CrossRefGoogle ScholarPubMed
Dupras, C, Ravitsky, V. The ambiguous nature of epigenetic responsibility. J Med Ethics. 2016; 42(8), 534541.CrossRefGoogle ScholarPubMed
Lappé, M. Epigenetics, media coverage, and parent responsibilities in the post-genomic Era. Curr Genet Med Rep. 2016; 4(3), 9297.CrossRefGoogle ScholarPubMed
Dolinoy, DC, Weidman, JR, Jirtle, RL. Epigenetic gene regulation: linking early developmental environment to adult disease. Reprod Toxicol. 2007; 23(3), 297307.CrossRefGoogle ScholarPubMed
Greally, JM. A user’s guide to the ambiguous word ‘epigenetics’. Nat Rev Mol Cell Biol. 2018; 19(4), 207208.CrossRefGoogle Scholar
Rothstein, MA, Cai, Y, Marchant, GE. The ghost in our genes: legal and ethical implications of epigenetics. Health Matrix. 2009; 19, 162.Google ScholarPubMed
Scott, S. Parenting quality and children’s mental health: biological mechanisms and psychological interventions. Curr Opin Psychiatry. 2012; 25(4), 301306.CrossRefGoogle ScholarPubMed
Richardson, SS, Daniels, CR, Gillman, MW, et al. Society: don’t blame the mothers. Nature. 2014; 512(7513), 131132.CrossRefGoogle ScholarPubMed
Nestler, EJ. Stress makes its molecular mark. Nature. 2012; 490(7419), 171172.CrossRefGoogle ScholarPubMed
Vanhees, K, Vonhogen, IG, van Schooten, FJ, Godschalk, RW. You are what you eat, and so are your children: the impact of micronutrients on the epigenetic programming of offspring. Cell Mol Life Sci. 2013; 71(2), 271285.CrossRefGoogle ScholarPubMed
Godfrey, KM, Lillycrop, KA, Burdge, GC, Gluckman, PD, Hanson, MA. Epigenetic mechanisms and the mismatch concept of the developmental origins of health and disease. Pediatr Res. 2007; 61(5 Part 2), 5R10R.CrossRefGoogle ScholarPubMed
Hughes, V. Epigenetics: the sins of the father. Nature. 2014; 507(7490), 2224.CrossRefGoogle ScholarPubMed
Gluckman, PD, Hanson, MA, Beedle, AS. Non-genomic transgenerational inheritance of disease risk. BioEssays. 2007; 29, 145154.CrossRefGoogle ScholarPubMed
Jirtle, RL, Skinner, MK. Environmental epigenomics and disease susceptibility. Nat Rev Genet. 2007; 8(4), 253262.CrossRefGoogle ScholarPubMed
Rothstein, MA. Epigenetic exceptionalism. J Law Med Ethics. 2013; 41(3), 733736.CrossRefGoogle ScholarPubMed
Chadwick, R, O’Connor, A. Epigenetics and personalized medicine: prospects and ethical issues. Per Med. 2013; 10(5), 463471.CrossRefGoogle ScholarPubMed
Moore, T, Arefadib, N, Deery, A, Sue West, M. The first thousand days: An evidence paper - Summary. (2017); Parkville, Victoria: Centre for Community Child Health, Murdoch Children’s Research Institute .Google Scholar
Lumey, LH, van Poppel, FWA. The dutch famine of 1944-45 as a human laboratory: Changes in the early life environment and adult health. In Early Life Nutrition, Adult Health and Development: Lessons from Changing Diets, Famines and Experimental Studies (eds. Lumey, LH, Vaiserman, A), 2013; pp. 5976. Nova Science Publishers, New York.Google Scholar
Jablonka, E, Lamb, MJ. The changing concept of epigenetics. Ann N Y Acad Sci. 2002; 981, 8296.CrossRefGoogle ScholarPubMed
Barker, D. The developmental origins of adult disease. J Am Coll Nutr. 2004; 23(sup6), 588S595S.CrossRefGoogle ScholarPubMed
Bay, JL, Mora, HA, Sloboda, DM, Morton, SM, Vickers, MH, Gluckman, PD. Adolescent understanding of DOHaD concepts: a school-based intervention to support knowledge translation and behaviour change. J Dev Orig Health Dis. 2012; 3(6), 469482.CrossRefGoogle ScholarPubMed
Roseboom, TJ, van der Meulen, JHP, Ravelli, ACJ, Osmond, C, Barker, DJP, Bleker, OP. Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Mol Cell Endocrinol. 2001; 185(1-2), 9398.CrossRefGoogle Scholar
Mameli, C, Mazzantini, S, Zuccotti, GV. Nutrition in the first 1000 days: the origin of childhood obesity. Int J Environ Res Public Health. 2016; 13(9), 838.CrossRefGoogle ScholarPubMed
Jacob, CM, Hanson, M. Implications of the Developmental Origins of Health and Disease (DOHaD) concept for policy-making. Curr Opin Endocr Metab Res. 2020; 13(supp1), 2027.CrossRefGoogle Scholar
Egger, G, Liang, G, Aparicio, A, Jones, PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004; 429(6990), 457463.CrossRefGoogle ScholarPubMed
Jiang, Y-H, Bressler, J, Beaudet, AL. Epigenetics and human disease. Annu Rev Genomics Hum Genet. 2004; 5(1), 479510.CrossRefGoogle ScholarPubMed
Peedicayil, J. The epigenome in personalized medicine. Clin Pharmacol Ther. 2013; 93(2), 149150.CrossRefGoogle ScholarPubMed
WHO. Noncommunicable Diseases: World Health Organization 2021, https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases.Google Scholar
Barker, D, Barker, M, Fleming, T, Lampl, M. Developmental biology: support mothers to secure future public health. Nature. 2013; 504(7479), 209211.CrossRefGoogle ScholarPubMed
Hanson, MA, Gluckman, PD, Godfrey, KM. Developmental epigenetics and risks of later non-communicable disease. In Hormones, Intrauterine Health and Programming. vol. 12, Seckl, JR, Christen, Y), 2014; pp. 175183. Springer International Publishing, Switzerland.CrossRefGoogle Scholar
Gluckman, PD, Hanson, MA, Low, FM. The role of developmental plasticity and epigenetics in human health. Birth Defects Res C Embryo Today. 2011; 93(1), 1218.CrossRefGoogle ScholarPubMed
Riley, L, Guthold, R, Cowan, M, et al. The World Health Organization STEPwise approach to noncommunicable disease risk-factor surveillance: methods, challenges, and opportunities. Am J Public Health. 2016; 106(1), 7478.CrossRefGoogle ScholarPubMed
Hanson, MA, Gluckman, PD. Developmental origins of health and disease - Global public health implications. Best Pract Res Clin Obstet Gynaecol. 2015; 29(1), 2431.CrossRefGoogle ScholarPubMed
Park, M, Kobor, MS. The potential of social epigenetics for child health policy. Can Public Policy. 2015; 41(Supplement 2), S89S96.CrossRefGoogle Scholar
Sharp, GC, Relton, CL. Epigenetics and noncommunicable diseases. Epigenomics. 2017; 9(6), 789791.CrossRefGoogle ScholarPubMed
Murray, R, Bryant, J, Titcombe, P, et al. DNA methylation at birth within the promoter of ANRIL predicts markers of cardiovascular risk at 9 years. Clin Epigenetics. 2016; 8(1), 16.CrossRefGoogle ScholarPubMed
Heyn, H, Méndez-González, J, Esteller, M. Epigenetic profiling joins personalized cancer medicine. Expert Rev Mol Diagn. 2013; 13(5), 473479.CrossRefGoogle ScholarPubMed
Weber, WW. The promise of epigenetics in personalized medicine. Mol Interv. 2010; 10(6), 363370.CrossRefGoogle ScholarPubMed
Fang, CY, Dunkel-Schetter, C, Tatsugawa, ZH, et al. Attitudes toward genetic carrier screening for cystic fibrosis among pregnant women: the role of health beliefs and avoidant coping style. Women’s Health. 1997; 3(1), 3151.Google ScholarPubMed
Rosenstock, IM. Why people use health services. Milbank Q. 1966; 44(3), 94127.CrossRefGoogle ScholarPubMed
Condit, CM. Public understandings of genetics and health. Clin Genet. 2010; 77(1), 19.CrossRefGoogle ScholarPubMed
Dubois, M, Louvel, S, Le Goff, A, Guaspare, C, Allard, P. Epigenetics in the public sphere: interdisciplinary perspectives. Environ Epigenet. 2019; 5(4), 5.CrossRefGoogle ScholarPubMed
Tercyak, KP, Hensley Alford, S, Emmons, KM, et al. Parents’ attitudes toward pediatric genetic testing for common disease risk. Pediatrics. 2011; 127(5), e1288e1295.CrossRefGoogle ScholarPubMed
Smerecnik, CMR, Mesters, I, de Vries, NK, de Vries, H. Educating the general public about multifactorial genetic disease: applying a theory-based framework to understand current public knowledge. Genet Med. 2008; 10(4), 251258.CrossRefGoogle ScholarPubMed
Fallat, ME, Katz, AL, Mercurio, MR, et al. Ethical and policy issues in genetic testing and screening of children. Pediatrics. 2013; 131(3), 620622.Google Scholar
Campbell, E, Ross, LF. Parental attitudes and beliefs regarding the genetic testing of children. Community Genet. 2005; 8(2), 94102.Google ScholarPubMed
Segal, ME, Polansky, M, Sankar, P. Adults’ values and attitudes about genetic testing for obesity risk in children. Int J Pediatr Obes. 2007; 2(1), 1121.CrossRefGoogle ScholarPubMed
Shkedi-Rafid, S, Fenwick, A, Dheensa, S, Lucassen, AM. Genetic testing of children for adult-onset conditions: opinions of the British adult population and implications for clinical practice. Eur J Hum Genet. 2015; 23(10), 12811285.CrossRefGoogle ScholarPubMed
Tarini, BA, Singer, D, Clark, SJ, Davis, MM. Parents’ interest in predictive genetic testing for their children when a disease has no treatment. Pediatrics. 2009; 124(3), e432e8.CrossRefGoogle ScholarPubMed
Etchegary, H, Dicks, E, Green, J, Hodgkinson, K, Pullman, D, Parfrey, P. Interest in newborn genetic testing: a survey of prospective parents and the general public. Genet Test Mol Biomarkers. 2012; 16(5), 353358.CrossRefGoogle ScholarPubMed
McKerracher, L, Moffat, T, Barker, M, Williams, D, Sloboda, DM. Translating the Developmental Origins of Health and Disease concept to improve the nutritional environment for our next generations: a call for a reflexive, positive, multi-level approach. J Dev Orig Health Dis. 2019; 10(4), 420428.CrossRefGoogle Scholar
Bay, JL, Vickers, MH, Mora, HA, Sloboda, DM, Morton, SM. Adolescents as agents of healthful change through scientific literacy development: a school-university partnership program in New Zealand. Int J STEM Educ. 2017; 4(1), 15.CrossRefGoogle ScholarPubMed
Bay, J, Vickers, M. Adolescent education: an opportunity to create a Developmental Origins of Health and Disease (DOHaD) circuit breaker. J Dev Orig Health Dis. 2016; 7(5), 501504.CrossRefGoogle ScholarPubMed
Bateson, P, Barker, D, Clutton-Brock, T, et al. Developmental plasticity and human health. Nature. 2004; 430(6998), 419421.CrossRefGoogle ScholarPubMed
Holliday, R. Epigenetics: a historical overview. Epigenetics. 2006; 1(2), 7680.CrossRefGoogle ScholarPubMed
Figure 0

Fig. 1. Alterations in DNA methylation status during cell development. Reused with permission from Jirtle and Skinner16. Global demethylation (and therefore epigenetic reprogramming) occurs at two key time points during development, during gametogenesis and early embryogenesis.