Environment, exposome and epigenetics: the molecular processes mediating risk, adaptation and resilience
Introduction to epigenetic mechanisms
Epigenetics encompasses the set of mechanisms that modulate gene expression without altering the DNA sequence. These processes include DNA methylation, histone modifications, chromatin remodeling, regulation by non-coding RNAs (such as microRNAs), and signaling mediated by extracellular vesicles (EVs). In particular:
DNA methylation stably regulates transcriptional accessibility and can be altered by environmental exposures in both site-specific and genome-wide manners.
Histone modifications (acetylation, methylation, phosphorylation, ubiquitination, etc.) shape chromatin states, defining permissive or repressive transcriptional configurations.
MicroRNAs regulate transcriptional and post-transcriptional networks, influencing proliferation, inflammation, metabolism and stress response.
Extracellular vesicles, including exosomes and microvesicles, function as true carriers of epigenetic information: they transport miRNAs, lncRNAs, proteins and bioactive lipids, enabling systemic cell–cell communication. EVs are particularly relevant in exposome research because they convey molecular signals derived from environmental exposures and physiological responses, contributing to the spread of pro-inflammatory, adaptive or protective phenotypes.
In this perspective, the epigenome is not an isolated layer but a dynamic, multilayered network integrating chemical, physical, metabolic and psychosocial stimuli.
Epigenetics as contextual reading of the environment
Epigenetic measures reflect the biological history of an individual more than any other omic level. The combination of DNA methylation, histone modifications, cellular microRNAs and EV-associated microRNAs allows researchers to:
infer functional states (inflammation, oxidative stress, ageing, tumor dormancy, immune surveillance);
identify temporal dynamics in response to acute or chronic exposures;
map individual biological trajectories rather than simple molecular snapshots.
Unlike the genome, the epigenome retains a plastic memory of environmental experience while preserving substantial adaptability.
Negative components of the exposome: risk and vulnerability
Air pollutants (PM2.5, NO2, black carbon), heavy metals, pesticides, volatile organic compounds, active/passive smoking, chronic stress, psychosocial factors and socioeconomic conditions can induce:
stable and transient alterations in DNA methylation;
pro-inflammatory or pro-senescence histone modifications;
dysregulated profiles of microRNAs, both cellular and EV-borne;
perturbations in EV-mediated intercellular communication affecting immunity, metabolism and ageing processes.
Hormesis: when a negative stimulus becomes adaptive
Within the exposome, not all potentially harmful exposures necessarily generate vulnerability. A key concept to interpret this complexity is hormesis, a biphasic biological response to a stimulus: the same exposure may produce detrimental effects at high doses but trigger adaptive or protective responses at low doses.
Hormesis is not a marginal phenomenon but a fundamental property of complex biological systems. At sub-toxic levels of a given environmental factor, the organism may activate stress-response pathways, antioxidant systems, compensatory metabolic circuits or epigenetic adaptation programs. These processes include:
temporary chromatin remodeling that facilitates transcription of cytoprotective genes;
modulation of microRNAs involved in damage control, proliferation and metabolism;
release of extracellular vesicles containing regulatory signals that coordinate systemic responses;
transient alterations in DNA methylation that prime cells to respond more efficiently to subsequent exposures.
Such responses are observed, for example, under low-grade oxidative stress, in certain metabolic exposures, during specific forms of physical activity and under intermittent environmental stimuli. Hormesis therefore represents an intersection between negative exposures and positive epigenetics: a mechanism through which minimal challenges can enhance overall resilience.
In the LETE framework, hormesis is important for two reasons. First, it helps distinguish exposures that produce cumulative damage from those that generate protective adaptation; second, it allows interpretation of some epigenetic changes not as markers of vulnerability but as indicators of efficient response systems.
Positive epigenetics: protective trajectories and biological resilience
An increasing body of literature supports the idea that the epigenome records not only damage but also protective biological processes:
physical activity induces epigenetic signatures that reduce systemic inflammation, modulate metabolism and slow biological ageing (PhActHealth, HEBE);
favourable environmental contexts (green exposure, air quality, public spaces) reduce pro-oxidative epigenetic patterns;
social relationships, adequate sleep and stress recovery modulate protective microRNAs, often EV-mediated;
diet and specific nutrients act as direct or indirect epigenetic modulators.
These changes are not trivial fluctuations but molecular signatures of resilience, capable of influencing disease trajectories and adaptive capacity.
The LETE framework: exposome-centric, multi-omic, interpretable
The LETE approach integrates:
DNA methylation (locus-specific, epigenome-wide, distribution-based);
profiles of cellular and circulating microRNAs, including those in EVs;
inflammatory and metabolic markers;
high-resolution environmental data (fixed/mobile sensors, geographic modelling);
measures of biological ageing (epigenetic clocks, inflammageing signatures);
advanced statistical models, including interpretable machine learning and causal inference.
The goal is to characterize biological trajectories, not just states, and to identify intervention points relevant to public health and preventive medicine — modifiable nodes of the exposome, functional biomarkers of risk and protection, and epigenetic mechanisms of adaptation.
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