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Molecular mechanisms of environmental exposures and human disease

Abstract

A substantial proportion of disease risk for common complex disorders is attributable to environmental exposures and pollutants. An appreciation of how environmental pollutants act on our cells to produce deleterious health effects has led to advances in our understanding of the molecular mechanisms underlying the pathogenesis of chronic diseases, including cancer and cardiovascular, neurodegenerative and respiratory diseases. Here, we discuss emerging research on the interplay of environmental pollutants with the human genome and epigenome. We review evidence showing the environmental impact on gene expression through epigenetic modifications, including DNA methylation, histone modification and non-coding RNAs. We also highlight recent studies that evaluate recently discovered molecular processes through which the environment can exert its effects, including extracellular vesicles, the epitranscriptome and the mitochondrial genome. Finally, we discuss current challenges when studying the exposome — the cumulative measure of environmental influences over the lifespan — and its integration into future environmental health research.

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Fig. 1: The exposome and multi-omic responses.
Fig. 2: Gene–environment interactions have an impact on disease phenotypes.
Fig. 3: Air pollution alters DNA methylation in genes that regulate expression of inflammatory cytokines.
Fig. 4: Environmental stressors affect DNA methylation age.
Fig. 5: Illustrative example of how air pollution can trigger coordinated epigenetic and epitranscriptomic responses that affect human health.
Fig. 6: Inhaled environmental exposures trigger extracellular vesicle signalling that mediates systemic inflammation and disease.

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Acknowledgements

The authors’ work was supported by grants from the National Institute of Environmental Health Sciences (P30ES009089, R35ES031688) and the National Center for Advancing Translational Sciences (TL1TR001875). The funding sources did not have any role in the writing of the manuscript or decision to submit for publication.

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H. W. and C. E. researched the literature. All authors contributed substantially to discussions of the content, wrote the article and reviewed and/or edited the manuscript.

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Glossary

Biological age

The physiological and functional status of an individual. The biological age may be older or younger than the chronological age and serves as a reflection of health and ageing.

Circular RNAs

Single-stranded RNAs in a closed continuous loop that are most often derived from protein-coding regions.

Compositional epistasis

A central requirement to demonstrate that there is a mechanistic gene–environment interaction that requires a study to show that some individuals will have the disease of interest if both environmental and genetic exposures are present but will not have the disease of interest if just one exposure is present. 

Crossover trial

A longitudinal study where all participants receive two or more treatments, often in random order and separated by a washout period.

Epigenome-wide association study

A genome-wide study of epigenetic changes such as DNA methylation and their association with a health outcome of interest.

Liquid biopsy

A peripheral blood test that can detect cells derived from specific types of tissue in the body.

Particulate matter

Microscopic particles of solid or liquid matter that are suspended in the air; fine particles have a diameter of ≤2.5 μm and are designated PM2.5.

Polygenic risk score

An estimate calculated as a weighted sum of many trait-associated alleles to summarize a person’s genetic liability of developing a disease of interest based on their genotype.

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Wu, H., Eckhardt, C.M. & Baccarelli, A.A. Molecular mechanisms of environmental exposures and human disease. Nat Rev Genet 24, 332–344 (2023). https://doi.org/10.1038/s41576-022-00569-3

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