Molecular and epigenetic markers as promising tools to quantify the effect of occupational exposures and the risk of developing non-communicable diseases

Abstract

Non-communicable diseases (NCDs) are chronic diseases that are by far the leading cause of death in the world. Many occupational hazards, together with social, economic and demographic factors, have been associated to NCDs development. Genetic susceptibility or environmental exposures alone are not usually sufficient to explain the pathogenesis of NCDs, but can be integrated in a more complex scenario that can result in pathological phenotypes. Epigenetics is a crucial component of this scenario, as its changes are related to specific exposures, therefore potentially able to display the effects of environment on the genome, filling the gap between genetic asset and environment in explaining disease development. To date, the most promising biomarkers have been assessed in occupational cohorts as well as in case/control studies and include DNA methylation, histone modifications, microRNA expression, extracellular vesicles, telomere length, and mitochondrial alterations.

Figure 1

The emerging field of “omics” includes a variety of large-scale data-rich biological measurements and provides new opportunities to better understand how occupational exposure, lifestyle factors and susceptibility factors can modulate disease risk

Figure 2

DNA methylation implies the addition of a methyl group to the fifth carbon of the cytosine DNA base, giving rise to a 5-methyl-cytosine. In differentiated cells, only cytosine followed by a guanine can be efficiently methylated by specific enzymes, called DNA methyltransferase. All the known DNA methyltransferases use S-adenosyl methionine (SAM) as the methyl donor. DNA methylation occurring in gene promoters can directly alter gene expression, by inhibiting the access to DNA of the transcriptional machinery function. This methylation is often referred as “gene-specific methylation”. Methylation taking place in repetitive transposable elements (e.g. Alu, LINE-1, HERVs, etc.) can compact the chromatin structure and therefore increase DNA resistance to toxicants

Figure 3

Human DNA is compacted by being wound around octamers of core histone proteins that form nucleosomes. Nucleosomes comprise 147 base pairs of DNA wrapped approximately twice around the protein core that contains two copies of each histone, H2A, H2B, H3, and H4. The interaction between DNA and histones is critical to regulating transcription, replication, and repair of the genome and is regulated by more than 100 distinct histone modifications, such as phosphorylation, methylation, ubiquitination, and acetylation. Histone code hypothesis states that gene regulation is partly dependent on histone modifications that primarily occur on histone tails. These modifications modify the net charge of the core histone, modulating the affinity between the DNA (negatively charged) and the octamer: adding positive charges would result in a closure of the nucleosome, while adding negative charges would result in an opening of the nucleosome

Figure 4

MicroRNAs are short RNAs of approximately 22 nucleotides in length. miRNAs post-transcriptionally regulate gene expression by silencing protein expression through cleavage and degradation of the mRNA transcript or inhibiting translation. A single miRNA can bind multiple mRNA targets (more than 100), while several miRNAs may regulate a single mRNA target

Figure 5

Extracellular vesicles are a heterogeneous group of membrane vesicles, including microvesicles and exosomes, which are released from cells under both physiological and pathological conditions. Extracellular vesicles play a central role in cell-to-cell communication, as they are able to transfer between cells biological active molecules, such as proteins and nucleic acids. Extracellular vesicles contain microRNAs, being able to modulate cell expression “at a distance”, and they have been detected in most body fluids, including blood, urine, saliva, cerebrospinal fluid, bronchoalveolar lavage fluid, amniotic fluid, seminal plasma, and breast milk

Figure 6

Telomeres are DNA repeat sequences (TTAGGG) that, together with associated proteins, form a sheltering complex that caps chromosomal ends and protects their integrity. Chromosomal stability is gradually lost as telomeres shorten with each round of cell division. Telomere length can be measured in leukocytes as marker of biological aging. In proliferating tissues, leukocyte telomere length is generally longer at birth and shortens progressively as individuals’ age. Most of the mammalian cells contain hundreds to more than a thousand mitochondria each. The mitochondrion works as a factory for ATP (adenosine triphosphate) and metabolite supplies for cell survival and releases cytochrome c to initiate cell death. Each organelle harbors 2–10 copies of mitochondrial DNA (mtDNA). mtDNA is known to be more sensitive to oxidative damage than nuclear DNA due to its lack of protective histones, introns, and an efficient DNA repair mechanisms. mtDNA copy number may serve as a promising biomarker for oxidative stress–related health outcomes