Abstract

Transgenerational epigenetic inheritance (TEI) is the transfer of epigenetic markers from parent to offspring that spans across multiple subsequent generations. A review of TEI will be conducted, followed by a discussion of innovative solutions to the problems that arise from the absence of sufficient knowledge on the topic. It is commonly believed that epigenetic markers are transferred from parents to their offspring, indicating that epigenetic modifications in the epigenome are also passed down through generations. These modifications occur through epigenetic processes, including DNA methylation, histone acetylation, methylation, and phosphorylation, which can be influenced by various external stimuli such as physical, chemical, and psychosocial factors. The purpose of this article is to increase awareness of the severe impacts of TEI on public and population health. Furthermore, this article presents an illustrative case study of TEI through exploring the effects of malnutrition during the Dutch Hunger Winter, a time of extreme famine at the end of the Second World War. With exposure to extreme famine, epigenetic markers were modified by affecting DNA methylation, histone modifications, and noncoding RNAs (ncRNA). These changes in the epigenetic markers led to differences in gene expression as well as cell function causing long-term, adverse side effects. The article reveals that increasing awareness of the apparent effects of TEI is integral to improving public health policies. The article demonstrates the need for future researchers to investigate how best to increase awareness of TEI for policymakers, healthcare professionals and the general public.

1. Introduction

1.1 Epigenetics

Epigenetic modification describes modifications that create chemical tags, which are attached to DNA and regulate gene expression (whether genes are ‘turned on’ or ‘turned off’, but which do not change the sequence of nucleotides in the DNA) (Barragan, 2020). These modifications are known as the epigenome and influence the production of proteins in cells. The epigenome has been found to be affected by positive experiences, such as healthy relationships and opportunities for learning, or adverse influences, including environmental toxins or stressful life circumstances, which leave a unique epigenetic “signature” on the genes. A recent study has found methods to reverse certain adverse “signatures” on children and restore healthy living, such as specific dietary recommendations (Meloni and Müller, 2018). Epigenetics is an emerging area of scientific research that shows how environmental influences affect the expression of genes and has implications for child development and long-term health outcomes, which will be discussed within this article.

1.2 Transgenerational epigenetic inheritance

The discovery of transgenerational epigenetic inheritance challenges the conventional idea that inheritance occurs solely through the DNA code passed from parent to offspring. This reveals that the effects of the conditions that an individual is exposed to can be passed down via epigenetic markers through the germline. These epigenetic markers are chemical modifications that occur through epigenetic processes, including DNA methylation, histone acetylation, methylation, and phosphorylation, which can be influenced by various external stimuli such as physical, chemical, and psychosocial factors (Loscalzo and Handy, 2011). The transfer of these markers from parents to their offspring may indicate that epigenetic modifications in the epigenome are also passed down through generations (Kaati et al., 2007).

TEI is a complex phenomenon that involves the interplay of genetic, environmental, and social factors across multiple generations. It is characterised as such only upon confirmation of epigenetic modifications having persisted through two generations on the paternal lineage and three on the maternal lineage (Wang and Allard, 2021). When considering alternative concepts within the field of inherited phenomena, intergenerational inheritance refers to traits that are passed directly from parent to offspring. However, intrauterine effects pertains specifically to events occurring during foetal development that influence health outcomes later in life (Yehuda and Lehrner, 2018). A noteworthy discovery in plants could demonstrate the effects of TEI in humans; many cases of TEI, such as paramutation in plants, protein based inheritance in yeast and inheritance of acquired traits in mice, have been documented since its discovery. In addition, dsRNA-mediated gene silencing in roundworms (Caenorhabditis elegans) has also been catalogued. The simplicity of studying plants must be taken into account because, in humans, the generational durations of TEI set by molecular mechanisms are still largely a mystery to molecular biologists (Perales et al., 2018).

1.3  Environmentally induced TEI

Environmentally induced epigenetic transgenerational inheritance of disease can result in phenotypic changes in both males and females, sparking considerable interest across a wide range of fields from plants to humans. The inheritance of diseases that lead to changes in phenotype can range from exposure to toxicants to nutrition. The ability of environmental exposure to influence multiple generations has been observed in all organisms studied, ranging from plants to humans. Epigenetic inheritance has been shown to impact hundreds of generations in plants, flies, and worms, while experiments in mammals have been limited to four to six generations so far. It is noteworthy that almost all environmental factors and toxicants studied have been demonstrated to facilitate epigenetic transgenerational inheritance (Korolenko et al., 2023).

Figure 1: Environmentally induced TEI (Korolenko et al., 2023).

Figure 1 shows a variety of environmental toxicants that influence a range of organisms, including plants, insects, mammals and birds. This visual representation highlights the broad impact of environmental factors on different species, emphasising the significance of understanding the effects of TEI across various organisms.

1.4  Importance of TEI on public health

TEI has significant implications for public health. Environmental factors, such as famine, chemical exposure, and varying social environments, can lead to transgenerational epigenetic changes, ultimately influencing disease susceptibility and long-term health. For instance, the administration of diethylstilbestrol (DES), a nonsteroidal oestrogen medication administered to pregnant women; originally prescribed for preventing miscarriage and related complications of pregnancy, has been linked to an increased risk of abnormalities and disease in subsequent generations (NCI, 2021). This specific finding underscores the potential impact of environmental factors on future generations’ epigenetic profiles and their susceptibility to not only complications in pregnancy, but also other potential chronic conditions such as obesity, diabetes, cardiovascular diseases, and mental health disorders. This article underlines the importance of global cooperation in addressing the challenges posed by TEI and in promoting a healthier future for generations to come. Raising awareness about TEI can lead to a re-evaluation of societal obligations, the implementation of laws and restrictions on certain drugs and chemicals, and the consideration of generational effects in public health regulations (Horsthemke, 2018). Furthermore, understanding TEI can help to develop strategies for disease prevention and intervention while prompting discussions on sustainable practices to safeguard the health of current and future populations. Taking a more proactive approach to spreading awareness about the health-associated effects of TEI can help foster a more renowned and cohesive approach to addressing the implications of TEI on public health.

2. Review of Literature

Epigenetics is defined as “the study of phenomena and mechanisms that cause chromosome-bound, heritable changes to gene expression that are not dependent on changes to DNA sequence” (Deans and Maggert, 2015). In simpler terms, epigenetics is the study of how environmental factors can modify a person’s epigenetic markers, resulting in differences in gene expression. This causes many alterations to a person’s health, both physical and psychological. Epigenetics can be broken down into three important mechanisms: (i) DNA methylation, an epigenetic process that suppresses gene expression, (ii) histone modification, the process by which histone-modifying enzymes alter histone substrates, in turn affecting gene expression, and (iii) non-coding RNAs (ncRNAs), which play a role in regulating gene expression.

Transgenerational epigenetic inheritance (TEI) is the scientific study of the epigenetic markers that are passed down from parent to subsequent generations. TEI not only discusses the complex mechanisms of the inheritance of epigenetic markers, but also how and what affects these epigenetic markers, including physical factors such as the type of food people eat and the amount of physical activity they perform. Chemical factors, such as the psychoactive drug nicotine, can influence histone proteins resulting in many differences in gene expressions. These can be passed down from the parent, resulting in the offspring and subsequent generations having a higher chance of developing multiple life-threatening diseases and conditions, such as cardiovascular diseases, metabolic disorders, obesity, as well as diabetes. Lastly, the psychosocial factors, the social environment that a person undergoes during the stages of life, are far less understood and can also have a lasting influence on epigenetic markers (Horsthemke, 2018). 

Studying and researching transgenerational epigenetic inheritance has proved to be a difficult task to present-day scientists because of its many obstacles and challenges. Due to the difficulty of studying multiple generations at once, both on the paternal and maternal side, gaining consent and acquiring data at this scale requires grand cooperation from willing participants and a great commitment from scientists. For this reason, researchers struggle to produce a large amount of accurate scientific data. Many problems arise from the lack of appropriate technology, sampling methods and accurate data analysis. Without a doubt, there is a complexity to conducting research on and studying TEI because of its plentiful factors and intertwined mechanisms (Fallet et al., 2023).

3. Case study

This section provides a demonstrative case study through which epigenetic inheritance and its effects have been observed, as well as an analysis of other factors in epigenetic modification.

3.1 The Dutch Hunger Winter

One example of a lifestyle factor affecting long term epigenetic markers was the Dutch Hunger Winter: the period of time in which famine was experienced by many in the Western Netherlands at the end of WWII, due to the German blockade that cut off food supplies from reaching the area. This provided an opportunity to study the implications of epigenetics changes and their long-term consequences on humans as it was well documented due to its recency and political importance. 

One paper investigated the correlation between famine, both in periconception (the period of time from before conception to the early periods of gestation) and in the later stages of gestation and levels of DNA methylation of the gene insulin-like growth factor II (IGF2) (Heijmans et al., 2008). The results suggested that exposure to famine conditions in periconception correlated with a significant decrease in DNA methylation of IGF2, but that timing of exposure is critical as exposure to famine in later stages of gestation did not decrease methylation of IGF2. Therefore, it has been concluded that, as only periconceptional exposure was related to IGF2 methylation, epigenetic modification may be particularly likely during the very early stage of mammalian development, which is a crucial period for establishing and maintaining epigenetic marks (Heijmans et al., 2008).

A second paper examined the effects of famine during foetal development on biological ageing throughout the individual’s life (Cheng et al., 2023). They used three biological age monitoring systems, or “epigenetic clocks”, DunedinPACE, GrimAge, and PhenoAge, to assess the speed of biological ageing amongst the Dutch Hunger Winter Family Study (DHWFS). This was a study that collected the survivors of in-utero famine as well as their same-sex siblings for comparison. It also collated a number of non-biologically related individuals born at a similar time in the same hospitals, or at the same time in areas unaffected by the famine, to use as a control group. They concluded that when using DunedinPACE to measure rate of biological ageing, there was an increased rate of biological ageing in survivors of in-utero exposure to famine when compared with the sibling control group and the unrelated control group. However, there was little connection between exposure to famine and rate of biological ageing when analysed using GrimAge and PhenoAge. They also found that the effects were more noticeable in female participants, and minimal in male participants. Unlike the study by Heijmans et al. (2008), they concluded that effects on the rate of biological ageing were more pronounced in those who experienced famine in later stages of gestation, contradicting the belief that periconception and early stages of gestation are particularly sensitive stages for developing foetuses. In fact, their data showed that “effect-sizes for DunedinPACE ranged from −0.01 to 0.18 and were somewhat larger for later gestational exposure windows”, demonstrating that epigenetic effects were more substantial later in gestation (Cheng et al., 2023). Although, for GrimAge and PhenoAge, “there were no gestational timing patterns in effect-sizes” (Cheng et al., 2023).

To conclude, famine is a key factor which causes changes in an individual’s epigenome, resulting in noticeable changes in the amount of DNA methylation as well as longer-term effects on the individual, such as changing the rate at which the individual ages.

Figure 2: Depiction of famine affecting epigenetic markers resulting in health risks (González-Rodríguez, Füllgrabe and Joseph, 2023).

3.2 General factors of epigenetic modification

Other factors can play a role in epigenetic modification, including chemical factors such as air pollutants, physical factors like diet, and many psychosocial factors like quality of life. This includes the interactions and environments that a person undergoes during their lifespan, ranging from everyday social interactions to the experiences faced during childhood.

Although the effects of malnutrition on the epigenome have been made clear by the research conducted on the Dutch Hunger Winter, there is also research that has contributed to the debate on whether or not a person’s diet can increase the risk of cancer (Heijmans et al., 2008). For example, a paper by Sapienza and Issa (2016) discussed the effects of diet on epigenetics and the potential subsequent impact on the cancer risk of an individual. The study concluded that, in animal models, there are well-researched and supported connections between diet and epigenetic modification. In fact, the article mentions that “the WCRF and the AICR have found convincing evidence that particular dietary components and cumulative dietary effects, such as obesity, are associated with several cancers” (Sapienza and Issa, 2016). Despite this and the conclusion that epigenetic modification is widely associated with cancer, no compelling evidence that dietary factors directly change an individual’s risk of cancer through epigenetic modification was found. This paper also considered how the relation between diet, epigenetics and cancer can be studied, stating that clear epigenetic modification and its consequences can be seen most clearly in extreme dietary conditions, such as famine events like the Dutch Hunger Winter. The study concludes that the more impactful study area concerning TEI is around less extreme dietary factors such as “high-fat Western diets”, due to its implications for public health (Sapienza and Issa, 2016).

Another lifestyle factor that can lead to epigenetic markers is substance abuse, such as non-medical use of tobacco, alcohol, and other recreational drugs. In the case of tobacco-smoking, associations between smoking and cardiovascular disease risk, as well as between smoking and epigenetic modification, have been documented. The hypomethylation of F2RL3, a gene which codes for proteinase-activated receptor 4, is particularly associated with smoking behaviour. “Proteinase-activated receptor 4 has been implicated in cardiovascular pathophysiology, especially inflammation, platelet function, and possibly perioperative myocardial injury after bypass surgery,” which suggests potential causation between smoking, epigenetic modifications, and cardiovascular diseases (Breitling, 2013). However, the exact nature of this causation is currently unknown, particularly as there may be a combination of connections between the factors affecting epigenetic processes. Some potential causation patterns between F2RL3 methylation are shown in Figure 3.

Figure 3: Possible causal structures showing associations between tobacco-smoking, F2RL3 methylation, and cardiovascular disease risk (Breitling, 2013).

Despite the unknown nature of this causality, the growing research in this field and the recent findings on this topic showing associations between lifestyle factors, such as smoking, epigenetic modification, and disease risk allows for improved prediction of disease risk and awareness of methods to prevent these diseases.

To summarise, there are many factors which can lead to epigenetic modifications, which can have vast and far-reaching implications for the health of an individual. Factors affecting the epigenome may be singular behaviours, such as smoking or consuming alcohol, or wider-reaching factors, such as diet or overall quality of life. Understanding these factors and their impact on long-term public health is crucial for improving health and wellbeing, so that researchers are better informed on how to prevent the increased disease risk that is due to epigenetic modifications. Also, we can make predictions relating to an individual’s health based on epigenetic markers. We should therefore emphasise the importance of good science communication to raise awareness on the science around the epigenome, including using public health information to improve the health of all.

4. Public health

4.1 Implications of TEI in public health

Public health refers to the health of the population as a whole, specifically as the subject of government regulation and support. It is linked to epidemiology, the study of health and disease in a population, and wide-spread disease prevention. 

In humans, an example of epigenetic multi-generational inheritance is the administration of diethylstilbestrol (DES), a nonsteroidal oestrogen medication to pregnant women (Nilsson and Skinner, 2015). In the past, DES was widely used for pregnancy support for patients with a history of miscarriage, menopausal symptoms and oestrogen deficiency. Studies have shown that the two subsequent generations following the female patients who consumed this medication presented a higher risk of abnormalities and an increased risk of disease (Nilsson and Skinner, 2015). This proves that transgenerational inheritance can be influenced by chemical factors. Whether they are necessary or not, our choices and decisions deeply impact not only the individual’s epigenetic markers, but those of subsequent generations as well. 

For there to be an environmentally-induced transgenerational epigenetic modification, these modifications must be present in the germline. This is because only germ cells, the reproductive cells for both males and females, are passed on from one generation to the next. Environmental exposure may induce alterations in DNA methylation during the development of germ cells, which are then transmitted from one generation to another (Nilsson and Skinner, 2015).

Figure 4: Depiction of epigenetic inheritance via the germline (Sharma, 2015).

More research has shown that ancestral exposure to vinclozolin, a powerful fungicide widely used on fruits, vegetables, and vineyards, has augmented disease susceptibility (Nilsson and Skinner, 2015). These diseases include prostate disease, kidney disease, mammary tumour development, immune maladies, anxiety, reproductive health disorders, and obesity. Interestingly enough, some tissues are more susceptible to exposure-induced germ cell epimutations and will thus develop diseases more often following these changes. Diseases such as cancer, obesity or prostate disease concern abnormal gene expression modifications in somatic cells. It is believed that the epimutations in the somatic cells are the ones that lead to increased disease susceptibility. Further research is needed to expand this topic further. 

Indeed, the possibility that epigenetic testing could inform people of their disease susceptibility demands immediate investigation. From a public health standpoint, considering the remarkable influence TEI has on the lives of populations around the world, epigenetic testing could further advance research and provide solutions to make a lasting impact on the health of all.

4.2 Chemical factors, restrictions must be implemented

The most notorious chemical substance that affects and alters epigenetic markers is the psychoactive drug, nicotine, that is present in tobacco. A psychoactive drug is a substance that affects how the brain works and causes a change in mood, awareness, thoughts, feelings, or behaviour (National Cancer Institute, 2024). Nicotine and cigarette smoke both cause histone acetylation, methylation, and phosphorylation, which are different types of epigenetic modification. Nicotine can have many health effects on the offspring of the person who smokes cigarettes. Through the germline, the modified epigenetic markers can be passed down to two subsequent generations, resulting in life-threatening diseases, such as coronary heart disease, diabetes and obesity (Gould, 2023). Opioids, medications with analgesic properties primarily used to relieve pain, can cause modifications to epigenetic markers by way of histone acetylation, leading to different unpredictable diseases, ranging from blood-related viruses like hepatitis B and C to heart infections, such as endocarditis (Centres for Disease Control and Prevention, 2021). Additionally, opioid abuse can result in a subsequent generation with a higher risk of developing an opioid addiction as a direct consequence of the parent abusing the substance (Browne et al., 2020). Public health institutions must address these issues, spread awareness about them, and, most importantly, implement heavier restrictions. In order to lay the groundwork for a healthier world, the chemical factors of epigenetic modifications should be taken with great precaution.

4.3 Physical factors that should be widespread

It has been well-documented that diet and physical activity are the top two physical factors that lead to changes in epigenetic markers in the human body. The amount of food people consume, the quality of food that is eaten, and the quantity of water ingested can all have lasting effects on epigenetic markers. Eating too much or too little can result in changes to the metabolism that can then result in alterations to epigenetic regulations (Hardy and Tollefsbol, 2011). The quality of the food people eat plays a huge role in their health. For example, in some cases, consuming an exceeding number of unhealthy foods may result in irreversible epigenetic changes that are passed down to multiple generations. Lack of proper hydration can result in inconsistencies in hydromineral homeostasis, in turn affecting epigenetic mechanisms that can be passed down from parent to offspring. Hydromineral homeostasis refers to the self-regulating process by which the osmotic properties of the plasma and proper tissue perfusion pressure are maintained through the ingestion and the urinary excretion of water and electrolytes, mainly sodium (Britannica, 2024). Physical activity plays the foremost role when discussing physical factors. The lack of proper and consistent physical exercise can affect epigenetic markers, leading to many health concerns that can be passed down through countless generations. For this reason, the physical factors that alter and change epigenetic markers should be properly discussed and addressed in public health, in order to decrease their negative impact on the world.

4.4 The severity of psychosocial factors

Psychosocial factors heavily affect epigenetic markers in ways that are sometimes unnoticeable and may be passed down to subsequent generations. These factors result from someone’s social environment and can have an important impact on their life. In fact, social environments can have an effect on someone mentally, but the effects to their epigenetic markers caused by these psychosocial factors are sometimes forsaken (Cunliffe, 2016). Social environments will dictate the physical and mental pillars that a person is built upon. If these environments are toxic and unwelcoming, then negative effects will be produced and transferred to generations. For example, a negative environment can impact an individual’s stress level, which, in turn, then affects their diet and leads to the altered epigenetic markers that are passed down through generations.  On the other hand, if the social environment is safe, secure, and welcoming, there is a higher chance of there being limited issues with someone’s epigenetic markers from a psychosocial aspect. To conclude, acknowledging the effects of our social actions in relation to TEI and public health should also be an important part of spreading awareness on the subject.

5. Discussion

We have highlighted the significance of TEI, a phenomenon that challenges the conventional understanding of genetic inheritance. The case study of the Dutch Hunger Winter that occurred during the Second World War and its negatively long-lasting effects on the epigenome of the people who suffered the consequences of it and their offspring are discussed. The case study shows significant evidence of physical lifestyle factors modifying the epigenome and how easy it is to affect future generations from choices, posing a challenge for public health and safety in the future. This article also discussed the implications of TEI in public health, including the administration of diethylstilbestrol (DES) to pregnant women, which has been linked to an increased risk of abnormalities and disease in subsequent generations. The Dutch Hunger Winter case study demonstrates that famine can be a key factor that causes changes in an individual’s epigenome, resulting in noticeable alterations in DNA methylation and longer-term effects on the individual, such as changing the rate at which the individual ages. This article underscored the importance of global cooperation in addressing the challenges posed by TEI and in promoting a healthier future for generations to come. Raising awareness about TEI can lead to a re-evaluation of societal obligation, as in the debate of how people should be held accountable for the damage that they may concur on themselves and future generations. Increased public awareness could also frame the scientific and societal issues found within TEI through the application of environmental justice principles, such as whether or not certain drugs should be easily accessible. If they are, various regulations could be further implemented, such as strict age restrictions, restrictions in the frequency of usage and more. The consideration of generational effects in public health regulations and studying TEI has proved to be a difficult task for present-day scientists because of its many obstacles and challenges, such as the arduous task of researching multiple generations at a time. As it is quite difficult to identify the direct correlations between the causes that affect gene expression patterns and the outcomes of such changes on an epigenetic and physiological level, researchers struggle to produce accurate scientific data. 

6. Conclusion

In summary, transgenerational epigenetic inheritance (TEI) plays a hidden and vital role in the lives of all. It is important for researchers to fully understand how the impact of an individual’s actions can affect epigenetic markers, and how these are consequently passed down to subsequent generations. It is also vital to be aware of the daily habits that are, more often than not, overlooked, as the fallout of the consequences can affect beyond the individual themselves.  A cohesive case study on the Dutch Hunger Winter, the time of extreme famine that the Dutch people were exposed to during the Second World War, provided scientists with the ability to accurately prove the effects of the environment on the epigenome. An individual’s choices regarding the implications of TEI in public health can help improve current lives and the ones of future generations. Due to the availability of common and intensely dangerous chemicals and substances, there have been, and will be, countless consequences due to regular consumption of these chemicals, as well as the risk of harmful exposure to others. It is thus vital to establish restrictions and laws to limit the exposure of these harmful mutagens. Furthermore, collaborating to adhere to said laws and restrictions is equally as important. Future research must be conducted to produce valid and accurate scientific epigenetic data, which can be achieved by developing the correct scientific methods and technologies. In order to create a safer and more sustainable future, researchers must fully comprehend the factors that affect epigenetic markers and take necessary action to prevent the widespread exposure to these factors worldwide.

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