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

Bladder cancer is the 9th most common cancer worldwide and patients often receive late diagnosis. Due to its high recurrence (50-80%) this malignancy is the fifth most expensive cancer in terms of total medical care expenditures. Even though epidemiologic evidence shows the etiologic link between occupational exposure to organic solvents and bladder cancer, not all exposed individuals develop such disease, making it an attractive target for prevention and risk stratification.

Previously, we reported the association between multiple polymorphisms in DNA-repair and metabolism genes and an increase in chromosome instability in workers exposed to organic solvents; however, it is still unclear whether gene-specific promoter methylation contributes to chromosome breakage or loss, as an intermediate end point of disease.

Here, we investigated the effect of chronic exposure to organic solvents and paints on DNA-methylation profiles and micronuclei frequency in non-smoking, car painter compared to age matched referents (non-exposed). Micronucleus frequency and methylation profiles in gene promoters of E-cadherin (CDH-1), p16INK4a, Glutathione S-transferase P (GSTP1), and Adenomatous polyposis coli (APC), were assessed in exfoliated urothelial cells from voided urine.

Poisson regression analysis indicated a significant increase in micronuclei frequency in all individuals with CDH-1- (RR 16.91, 95% CI 8.2-35.76, p< 0.001) and GSTP1- (RR 2.23, 95% CI 1.58-3.12, p< 0.001) promoter methylation. In addition, exposed workers with methylated p16INK4a promoter had an increased micronuclei frequency in relation to the matched referents (RR 1.93, 95% CI 1.45-2.55, p< 0.001). In contrast, methylation in the APC promoter was associated with decreased micronuclei frequency in all individuals (RR 0.11, 95% CI 0.7-0.19, p< 0.001). Finally, overall the exposed group had a higher percentage of individuals with > 2 micronuclei/2000 cells compared to the referent group (p = 0.04). These results support the conclusion that gene-specific promoter methylation may increase micronuclei frequency in a dependent or independent interaction with occupational exposure to organic solvents. The present and other studies might be used in the primary prevention of bladder cancer to encourage preventive measures at the work place and lifestyle changes in those at highest risk of developing the disease.