The background of our hypothesis

Environmental impact on health and the Exposome

According to the WHO (World Health Organization), an estimated 24% of the global disease burden and 23% of all deaths can be attributed to modifiable environmental factors, as disease often results from interactions between genes and the environment experienced throughout the life course. Environmental threats to human health include numerous environmental pollutants including metals, phytoestrogens, polycyclic aromatic hydrocarbons, dioxin-like chemicals, polychlorinated biphenyls, phthalates, and several classes of pesticides. However, environmental exposures cannot be limited to the above-mentioned toxicants, as it is becoming increasingly clear that non-conventional exposures (e.g., stressful events, social life, and parental care) can modulate disease risk.

The state of health/disease is synergistically modulated by a multitude of factors, as explained by the concept of “exposome,” first defined in 2005 by Chris Wild. The exposome includes the totality of human disease determinants encountered during the life course, and can be divided into three main domains:

1. The internal environment, e.g., metabolism, endogenous circulating hormones, morphology, physical activity, gut microflora, inflammation, lipid peroxidation, oxidative stress, and aging;
2. Specific external exposures, e.g., radiation, infectious agents, chemical contaminants and environmental pollutants, diet, lifestyle factors, tobacco, alcohol, occupation, and medical interventions;
3. The general external exposome, that includes the wider social, economic, and psychological influences on the individual (e.g. social capital, education, financial status, psychological and mental stress, urban-rural environment, and climate).

The exposomic concept aims to track an individual’s exposures from preconception to death in order to elucidate how environmental, dietary, and lifestyle factors interact with genetic background. However, to date, no standardized methods exist to comprehensively characterize the exposome. One of the major challenges arises from the complex interconnections among exposures, as their health effects are not independent but are shaped by their interactions. Although analytical techniques are continually improving, simultaneously assessing such a large number of factors across extensive study populations remains highly challenging. Moreover, conducting a comprehensive follow-up of a human cohort over an entire lifespan is extremely difficult.

Despite our limited capability to fully track and disentangle all exposomic information, our DNA can retain a molecular record of the stimuli encountered throughout the life course. A growing compendium of evidence indicates that the exposome might induce epigenetic modifications, particularly alterations in DNA methylation patterns. Although the relative contribution of epigenetics to disease development is only partially understood, environmental epigenetics (i.e., the epigenetic pattern shaped by environmental exposures) holds great promise as a biomarker that may easily assess and summarize all lifestyle habits and environmental exposure effects.

Environmental epigenetics

Epigenetic mechanisms are flexible processes that change genome function under exogenous influences, and also allow the stable propagation of gene activity states in the context of the same DNA sequence. Among epigenetic mechanisms, DNA methylation covalently modifies cytosine to form 5-methylcytosine, which represents 2–5% of all cytosines in mammalian genomes and is found primarily on CpG dinucleotides. Clusters of CpG dinucleotide (the so called “CpG islands”) are typically located in gene promoters, where they play a regulatory role in gene activation or silencing. However, the majority of CpG sites in the genome are located within repetitive elements (REs). DNA methylation was thought to be a stable and permanent epigenetic modification. However, studies on active DNA demethylation have overturned this view, revealing DNA methylation as a dynamic and reversible process. Its plastic nature allows it to respond to environmental stimuli, enabling cells to adapt to changing conditions.

If on the one hand, previous studies have had the great merit of demonstrating the link between exposures and modification of DNA methylation, on the other hand, they have been either too narrowly focused on specific pathogenetic mechanisms or, on the contrary, too broad (e.g., genome-wide associations) and consequently difficult to interpret.

The role of repetitive elements

Besides its well-known role in altering gene expression, DNA methylation also has an important function in the maintenance of genome integrity. This role is executed primarily through the methylation of repetitive DNA sequences and endogenous transposons. These REs are low-complexity sequences of nucleic acids occurring in multiple copies throughout the genome, which can be divided into two groups based on the presence or absence of long terminal repeats (LTRs). Non-LTR elements include short interspersed nuclear elements (SINEs, e.g., Alu) and long interspersed nuclear elements (LINEs). The majority of LTR elements are derived from human endogenous retroviruses and represent about 8% of the human genome.

The potential impact of altered RE methylation is underscored by the fact that these elements constitute up to 40% of the human genome, and have been shown unequivocally to be activated under certain conditions. Notably, increasing evidence shows that REs are frequently hypomethylated in various human pathologies, including cancer, cardiovascular and respiratory diseases, and psychiatric disorders, as well as in the aging process.

Although REs were historically dismissed as “junk” DNA, the high proportion of these sequences in our genome and their responsiveness to environmental and biological stimuli, demonstrate the need for a paradigm shift to interpret current scientific evidence to understand the functions of REs and how they promote disease development. REs could function as dynamic elements that mediate physiological adaptability to environmental inputs, aligning with the concept of the exposome, i.e. the cumulative impact of all internal and external factors across an individual’s lifetime.