DNA methylation as a potential mediator between environmental pollutants and osteoporosis; a current hypothesis.

To Editor, Osteoporosis is a complex non-communicable disease, known as a silent disease, characterized by low bone mass and increased risk of fracture in multiple sites of the body. The worldwide prevalence of osteoporosis is estimated to be 18.3%.1 As a public health concern, osteoporosis is related to remarkable morbidity and mortality rates as well as huge economic costs for the medical system globally. Osteoporosis is thought to have developmental origins in early life.2 Some well-known modifiable or non-modifiable risk factors of osteoporosis consist of age, female gender, inactivity, poor diet, stress, and smoking. A growing body of evidence showed that exposure to different classes of environmental pollutants might be related to low bone mass or increased risk of osteoporosis.3-5 A recent metaanalysis revealed that, unlike mercury, cadmium and lead exposure is associated with an increased risk of osteoporosis or osteopenia (odds ratios = 1.35 and 1.15, respectively).4 Considering air pollution, in line with other research, a recently published study found that in the UK, exposure to particulate matter 2.5 micrometers or less in diameter (PM2.5), nitrogen dioxide (NO2), and nitrogen oxides (NOx) is associated with an increased risk of osteoporosis in 422,955 individuals.6 We had previously summarized the findings on the association of air pollution with bone mass.7 In addition, emerging evidence indicated the detrimental effects of some environmental chemicals, such as perfluoroalkyl substances (PFASs) and phthalates on bone mineral density.5 The underlying pathophysiological mechanisms involved in bone response to environmental pollutants are complex and remain to be determined. Those mechanisms include but are not limited to, induction of pro-inflammation, oxidative stress, and endocrine disruption.4,5 All around the world, humans are exposed to environmental pollutants and are susceptible to their adverse health outcomes. Epigenetics is the study of heritable changes in gene expression resulting from mechanisms other than changes in the DNA sequence and is crucial in determining spatiotemporal patterns of gene expression.8 DNA methylation (DNAm) includes the addition of a methyl group to cytosine residues of CpG dinucleotides. DNAm is often linked to turning off genes. This happens when transcription factors that control gene activity are unable to bind to it or when specific proteins that stop gene activity get attracted to it.9 An accumulating line of evidence supports the pivotal action of epigenetic mechanisms, including DNA methylation, in the influence of environmental chemicals on the disease burden. The effects of epigenetic changes have been linked not only to the prenatal period but also to adulthood. A systematic review proposed a possible role of exposure to cadmium, lead, and persistent organic pollutants (POPs) on DNAm changes.10 Likewise, a literature review of the last 3 years revealed strong evidence between prenatal metal exposure (especially lead and cadmium) and DNAm signatures. Such an association has been supported for adults as well.11 Moreover, several air pollutants such as black carbon (BC), particulate matter (PM), ozone (O3), NOx, and polycyclic aromatic hydrocarbons (PAHs) are found to be linked to changes in DNAm across the life span and adverse health outcomes. i.e., DNAm is thought to be typically lowered after exposure to air pollution.12 In one study, each 10 μg/ m3 increase in prenatal exposure to particulate matter 10 micrometers or less in diameter (PM10), has been associated with a 1.78% decrease in the placental LINE1 methylation,