In this review, we discussed the genetic and epigenetic influences on the cellular response to PM, DEP in particular. Although progress has been made, many questions remain ().
Summary and remaining questions.
Genome wide association studies (GWAS) represent a powerful tool for investigating the genetics of common diseases and have successfully identified several genetic variants associated with exposure to air particulates. However, findings from these studies are largely limited to common or imputed single nucleotide polymorphisms, which likely confer small increases in risk87
. Rarer variants present in less than 5% of population that are poorly detected by available genotyping arrays possibly have larger effects. In order to more fully define the genetic influence that modifies responses to environmental pollutants, longitudinal studies designed to assess early life exposure are required. Non-SNP variants including copy number variation and copy neutral variation need to be included in future studies. Identification of rare variants by exome or whole genome sequencing, use of shared datasets provided by the 1000 Genomes Project, and the design of meta-studies with consistently well-defined phenotypes across large population sets will greatly advance the development of genetic studies.
How PM causes epigenetic changes is an intriguing question. Genetic variations in glutathione-s-transferases (GSTP1
) have been identified as potential modifiers of the responses to PM. GSTs represent a major group of detoxification enzymes, and their substrate glutathione (GSH) is produced through transsulfuration pathway from cysteine, which is connected with the methylation cycle and the folate cycle (). In conditions with high oxidative stress and low GSH, such as autism88
and severe asthma89
, the enhanced need to synthesize GSH could potentially impair biosynthesis of SAM (S-adenoylmethionine, the major methyl donor for most methyltransferases that modify DNA, RNA, histones and other proteins) and perturb DNA methylation90
. In support of this, diets lacking sources of methyl-groups (folic acid, B12, choline and betaine) result in global and gene-specific DNA hypomethylation91
. DEP exposure itself can contribute to oxidative stress; in vitro
exposure to DEP induced a decrease in the cellular GSH:GSSG ratio31
. Thus in early life, this may be a mechanism by which PM could affect global and specific gene methylation. One might postulate that PM may influence the methylation cycle by depleting glutathione, thus promoting epigenetic changes. It is also been proposed that oxidative stress can affect global epigenetic patterns by interfering with metabolism, and thereby activating TET and other chromatin modifiers92
. Moreover, histone acetylation changes induced by DEP in vitro
can be countered in part by the addition of antioxidants72
, thus, there may be an opportunity for targeted intervention in high risk infants aimed at disease prevention.
Potential mechanism by which PM affects epigenome
An epigenetic origin of disease has been suggested based on the observations linking early life exposure with later disease. Birth cohort studies have revealed that early life exposure (before age 1) to DEP leads to persistent wheezing37, 38
. It will be necessary to determine the developmental origins of this susceptibility in order to develop interventions aimed at prevention of disease during this critical window in early life. Epigenetic patterns associated with specific environmental pollutants may be useful biomarkers to determine the long-term effects of early exposure to environmental pollutants on human health, although many questions remain to be answered6
. Epigenetic modifications may turn on or off gene expression inappropriately; or may mask or unmask DNA sequence variation that has disease consequences. Studies in twins and healthy controls identified genetic variations that were associated with nearby differences in DNA methylation93
. In the same study, the heritability estimate in DNA methylation at 96 CpG sites out of 431 CpG sites examined was as high as 94%. Therefore, integrating epigenetics into genetics studies to study their influences on responses to environmental pollutants will greatly help to identify risk factors and better understand the pathogenesis of diseases associated with environmental pollution.
To study epigenetic makers associated with environmental pollutants, the most optimal epigenetic methodology has to be utilized. Research to date has been utilizing methylation of repeat elements as indicators of global methylation. Whether methylation of repeat elements can be used as markers for pathological diseases or specific exposure requires further investigation because the methylation status of these elements is influenced by inter-individual variability and gender specific variation94, 95
. With the development of newer technologies, more discovery-oriented approaches can be utilized to identify epigenetic responses to air pollutants. Statistical tools and concepts are being developed to analyze, interpret and compare population-level epigenetic data. Another limitation of environmental epigenomic studies is sample choice. The most common samples studied include blood, buccal cells, cord blood and skin cells. Whether these are legitimate surrogate tissues for airway cells needs to be carefully evaluated. Continued research is necessary to understand how DEP is recognized in the airways and what cellular pathways initiate and mediate innate and adaptive immune responses to DEP that promote adverse health effects.