Gene-specific promoter methylation is associated with micronuclei frequency in urothelial cells from individuals exposed to organic solvents and paints

Abstract

Sufficient epidemiologic evidence has established an etiologic link between bladder cancer risk and occupational exposure as a painter to organic solvents. Currently, it remains to be established whether gene-specific promoter methylation contributes to bladder cancer development, including by enhancing chromosome breakage or loss. We investigated the effect of chronic exposure to organic solvents and paints on DNA methylation profiles in the promoter regions of four genes (GSTP1, p16(INK4a), APC and CDH1) and micronucleus (MN) frequency in exfoliated urothelial cells from voided urine from Colombian male non-smoking car painters and age-matched unexposed individuals. The exposed group had a higher percentage of individuals with >2 MNs/2000 cells compared with the unexposed group (P=0.04). Gene-specific analysis showed a significantly higher percentage of individuals with methylated GSTP1, p16(INK4a) and APC in the exposed group. Poisson regression analysis indicated that exposed individuals with methylated GSTP1 and p16(INK4a) promoters were more than twofold more likely to have an increase in MN frequency as compared with the reference. Finally, among exposed individuals with GSTP1 and p16(INK4a) methylated promoters, those with a greater age had a higher RR of increased MN frequency compared with younger exposed individuals with methylated promoters. These results support the conclusion that gene-specific promoter methylation may increase MN frequency in a dependent or independent interaction with occupational exposure to organic solvents.

Micronuclei frequency in urothelial cells of bladder cancer patients, as a biomarker of prognosis

“…In this context, the detection of increased levels of MN in urothelial cells can be a useful approach to detect individuals prone to have bladder cancer, and/or to assess the prognosis of the pathology. Increased MN frequencies in urothelial cells of humans populations have been associated to those risk factors involved in bladder cancer such as tobacco (Zamani et al, ), arsenic (Paul et al, ), and occupational exposure to organic solvents (Hoyos‐Giraldo et al, ). Additionally, MN formation was detected in the bladder cells of rats exposed to orto‐phenylphenol, a fungicide and antibacterial agent well known as a bladder tumor inducer in rats (Balakrishnan and Eastmod, ).…”

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

“…A study conducted in 150 non-smoking car painters from several workshops in the southwest of Colombia found a significant increase in DNA methylation in the promoter region of GSTP1 and p16 INK4a in exfoliated urothelial cells of exposed workers compared to references, and these gene-specific alterations were associated with an increase in micronuclei frequency [202], an indicator of genotoxicity. Because the exact chemical composition of the exposure is not reported here, the molecular findings can only be associated to the general category “occupational exposure as a painter,” which is one of the occupational exposures included in the IARC monograph volume 100F.…”

Increased DNA Damage, Instability and Cytokinesis Defects in Occupationally Exposed Car Painters

“…Particularly, Moro et al (24) observed an increase in oxidative damage in car painters. Recently, Hoyos-Giraldo et al (16) observed an association between years of occupational exposure as a painter and organic solvents levels in urothelial cells. As a matter of fact, some studies have already shown a positive association between car painting and DNA damage (25,26), but as far as we know, our study is the first to evaluate the occupational exposure of car painters using a multimarker test as BMCyt, unravelling not only the DNA damage status, but also potential cellular phenotypes associated with genome instability and alterations in the cellular kinetics as early biomarkers for future disease and cancer risk.…”

“…Finally, it is disturbing to know that literature is full of reports associating painting with cancer, especially considering that >90% of all human cancers are of epithelial origin (16,17,28). Recently, Jung et al (28) observed that Canadian painters occupationally exposed had high risk of lung cancer, corroborating the IARC classification.…”

“…The International Agency for Research on Cancer (IARC) already classified commercial painting as a high-risk group for lung and bladder cancer development (14), whereas the major pathways of exposure involve inhalation of vapors and gases, dermal absorption and/or ingestion (15). While, benzene is already classified by IARC as "carcinogenic to humans", isocyanates, toluene and xylene per se are classified as "not classified as to their carcinogenicity in humans", even with the crescent literature associating painters with chemical contamination and diseases (16,17). Another major issue is that some workers do not even know about these classifications, so they tend to ignore personal and collective protective equipment, what could increase the risk for future diseases.…”