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.

Figure 1.. Gene-environment interactions impact disease phenotypes.

When gene-environment interactions exist, environmental exposures confer differing levels of disease risk for individuals with different genotypes. In this example, the glutathione S-transferase gene (GSTM1) encodes detoxifying enzymes that defend against oxidative stress. The gene has null alleles that cause loss of enzyme activity. Recent studies have shown that carriers of GSTM1 null alleles who were exposed to indoor air pollution experienced increased risk of asthma and lung function impairment compared to participants with functional GSTM1 alleles. This example highlights the importance of evaluating gene-environment interactions to identify SNPs that alter disease risk in the presence of prevalent environmental insults.

Figure 2.. Air pollution alters DNA methylation in genes that regulate expression of inflammatory cytokines.

When particulate matter (PM) air pollution is inhaled into the lungs, small particles disrupt epithelial cell integrity in the lungs and trigger neutrophil chemotaxis and production of reactive oxygen species (ROS). Oxidative species reduce DNA methyltransferase activity, catalyze oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, and decrease expression of methionine adenosyltransferase 1A, thereby reducing availability of biologic methyl donors. These effects lead to pollution-related alterations in DNA methylation, including demethylation in the promoter region of genes in the mitogen-activated protein kinase (MAPK) pathway. These alterations hinder DNA methylation-mediated suppression of inflammatory genes and link air pollution exposure to the production of pro-inflammatory cytokines.

Figure 3.. Environmental stressors impact DNA methylation age.

Epigenetic aging clocks encompass CpG sites that estimate DNA methylation age of human tissue. Harmful environmental exposures including fine particulate matter air pollution, organochlorine pesticides, and polycyclic aromatic hydrocarbons are associated with epigenetic age acceleration. In contrast, improved diet quality and higher socioeconomic status are associated with epigenetic age deceleration. Epigenetic age acceleration leads to genomic instability and aberrant gene expression and is associated with aging-related diseases and functional decline.

Figure 4.. One example of how air pollution can trigger coordinated epigenetic and epitranscriptomic responses that impact human health.

Exposure to particulate matter air pollution can trigger alterations in epitranscriptomic machinery and multiple other regulatory mechanisms that interact to generate a systemic response. In this example, air pollution exposure triggers changes in DNA methylation, small non-coding RNA, and epitranscriptomic machinery that may influence risk of pulmonary fibrosis.

Figure 5.. Inhaled environmental exposures trigger EV signaling that mediates systemic inflammation and disease.

Particulate matter inhalation triggers alveolar macrophages and airway epithelial cells to release pro-inflammatory EVs. Ultrafine particles also enter the systemic circulation and trigger EV release from endothelial cells, platelets, and circulating blood leukocytes. EVs amplify production of inflammatory cytokines and enhance recruitment of inflammatory cells. As a result, circulating EVs create a cycle that intensifies inflammation and can lead to end organ dysfunction including lung function impairment, atherogenesis, and neurodegeneration.

Figure 6.. Exposomics and multi-omic responses.

The exposome is the cumulative measure of environmental influences including the external environment, lifestyle, behavior, and diet and the resulting biological and endogenous processes. The exposome induces biological responses at every level and should be integrated into multi-omic studies. Ultimately, the complex non-linear interactions between the environment and our genome, epigenome, transcriptome, metabolome, and proteome drive the aging process and the pathogenesis of chronic diseases.