LINE-1 methylation in granulocyte DNA and trihalomethane exposure is associated with bladder cancer risk

DNA methylation changes contribute to bladder carcinogenesis. Trihalomethanes (THM), a class of disinfection by-products, are associated with increased urothelial bladder cancer (UBC) risk. THM exposure in animal models produces DNA hypomethylation. We evaluated the relationship of LINE-1 5-methylcytosine levels (LINE-1%5mC) as outcome of long-term THM exposure among controls and as an effect modifier in the association between THM exposure and UBC risk. We used a case-control study of UBC conducted in Spain. We obtained personal lifetime residential THM levels and measured LINE-1%5mC by pyrosequencing in granulocyte DNA from blood samples in 548 incident cases and 559 hospital controls. Two LINE-1%5mC clusters (above and below 64%) were identified through unsupervised hierarchical cluster analysis. The association between THM levels and LINE-1%5mC was evaluated with β regression analyses and logistic regression was used to estimate odds ratios (OR) adjusting for covariables. LINE-1%5mC change between percentiles 75^th and 25^th of THM levels was 1.8% (95% confidence interval (CI): 0.1, 3.4%) among controls. THM levels above vs. below the median (26 μg/L) were associated with increased UBC risk, OR = 1.86 (95% CI: 1.25, 2.75), overall and among subjects with low levels of LINE-1%5mC (n = 975), OR = 2.14 (95% CI: 1.39, 3.30), but not associated with UBC risk among subjects’ high levels of LINE-1%5mC (n = 162), interaction P = 0.03. Results suggest a positive association between LINE-1%5mC and THM levels among controls, and LINE-1%5mC status may modify the association between UBC risk and THM exposure. Because reverse causation and chance cannot be ruled out, confirmation studies are warranted.     

DNA methylation levels and long-term trihalomethane exposure in drinking water: an epigenome-wide association study

Trihalomethanes (THM) are undesired disinfection byproducts (DBPs) formed during water treatment. Mice exposed to DBPs showed global DNA hypomethylation and c-myc and c-jun gene-specific hypomethylation, while evidence of epigenetic effects in humans is scarce. We explored the association between lifetime THM exposure and DNA methylation through an epigenome-wide association study. We selected 138 population-based controls from a case-control study of colorectal cancer conducted in Barcelona, Spain, exposed to average lifetime THM levels ≤85 μg/L vs. >85 μg/L (N = 68 and N = 70, respectively). Mean age of participants was 70 years, and 54% were male. Average lifetime THM level in the exposure groups was 64 and 130 µg/L, respectively. DNA was extracted from whole blood and was bisulphite converted to measure DNA methylation levels using the Illumina HumanMethylation450 BeadChip. Data preprocessing was performed using RnBeads. Methylation was compared between exposure groups using empirical Bayes moderated linear regression for CpG sites and Gaussian kernel for CpG regions. ConsensusPathDB was used for gene set enrichment. Statistically significant differences in methylation between exposure groups was found in 140 CpG sites and 30 gene-related regions, after false discovery rate <0.05 and adjustment for age, sex, methylation first principal component, and blood cell proportion. The annotated genes were localized to several cancer pathways. Among them, 29 CpGs had methylation levels associated with THM levels (|Δβ|≥0.05) located in 11 genes associated with cancer in other studies. Our results suggest that THM exposure may affect DNA methylation in genes related to tumors, including colorectal and bladder cancers. Future confirmation studies are required.     

LINE-1 methylation in granulocyte DNA and trihalomethane exposure is associated with bladder cancer risk

DNA methylation changes contribute to bladder carcinogenesis. Trihalomethanes (THM), a class of disinfection by-products, are associated with increased urothelial bladder cancer (UBC) risk. THM exposure in animal models produces DNA hypomethylation. We evaluated the relationship of LINE-1 5-methylcytosine levels (LINE-1%5mC) as outcome of long-term THM exposure among controls and as an effect modifier in the association between THM exposure and UBC risk. We used a case-control study of UBC conducted in Spain. We obtained personal lifetime residential THM levels and measured LINE-1%5mC by pyrosequencing in granulocyte DNA from blood samples in 548 incident cases and 559 hospital controls. Two LINE-1%5mC clusters (above and below 64%) were identified through unsupervised hierarchical cluster analysis. The association between THM levels and LINE-1%5mC was evaluated with β regression analyses and logistic regression was used to estimate odds ratios (OR) adjusting for covariables. LINE-1%5mC change between percentiles 75^th and 25^th of THM levels was 1.8% (95% confidence interval (CI): 0.1, 3.4%) among controls. THM levels above vs. below the median (26 μg/L) were associated with increased UBC risk, OR = 1.86 (95% CI: 1.25, 2.75), overall and among subjects with low levels of LINE-1%5mC (n = 975), OR = 2.14 (95% CI: 1.39, 3.30), but not associated with UBC risk among subjects’ high levels of LINE-1%5mC (n = 162), interaction P = 0.03. Results suggest a positive association between LINE-1%5mC and THM levels among controls, and LINE-1%5mC status may modify the association between UBC risk and THM exposure. Because reverse causation and chance cannot be ruled out, confirmation studies are warranted.     

Impacts of drinking water pretreatments on the formation of nitrogenous disinfection by-products

The formation of disinfection by-products (DBPs), including both nitrogenous DBPs (N-DBPs) and carbonaceous DBPs (C-DBPs), was investigated by analyzing chlorinated water samples following the application of three pretreatment processes: (i) powdered activated carbon (PAC) adsorption; (ii) KMnO(4) oxidation and (iii) biological contact oxidation (BCO), coupled with conventional water treatment processes. PAC adsorption can remove effectively the precursors of chloroform (42.7%), dichloroacetonitrile (28.6%), dichloroacetamide (DCAcAm) (27.2%) and trichloronitromethane (35.7%), which were higher than that pretreated by KMnO(4) oxidation and/or BCO process. The removal efficiency of dissolved organic carbon by BCO process (76.5%)--was superior to that by PAC adsorption (69.9%) and KMnO(4) oxidation (61.4%). However, BCO increased the dissolved organic nitrogen (DON) concentration which caused more N-DBPs to be formed during subsequent chlorination. Soluble microbial products including numerous DON compounds were produced in the BCO process and were observed to play an essential role in the formation of DCAcAm in particular.     

Trihalomethanes in desalinated water: Human exposure and risk analysis

Desalinated seawater is used to satisfy domestic water demands in many countries. The treated freshwater is blended with desalinated water to increase the water supply. The desalinated and blended water contains disinfection byproducts (DBPs), some of which may induce cancer risk to human. In this study, concentrations of trihalomethanes (THMs) in desalinated and blended water in Saudi Arabia were investigated, and human exposure and risk were predicted. The intakes of THMs (chloroform, bromodichloromethane, dibromochloromethane, and bromoform) were predicted to be 8.38 × 10^?5, 7.57 × 10^?5, 2.54 × 10^?5, and 4.32 × 10^?4 mg/kg-d, respectively. The overall cancer risk and hazard index were estimated to be 1.78 × 10^?5 (range: 7.40 × 10^?7–9.26 × 10^?5) and 3.49 × 10^?2 (range: 1.20 × 10^?3–2.34 × 10^?1), respectively. The probabilities of cancer risk exceeding the risk levels of 1 × 10^?6, 1 × 10^?5, and 5.0 × 10^?5 were 1.0, 0.775, and 0.012, respectively. The loss of disability adjusted life years (DALYs) was predicted to be 25.1 per year while the cancer risk represented 8.48 × 10^?7 DALY per person per year. The financial burden from such risk was estimated to be US$ 2.72 (range: US$ 2.52–2.91) million per year. The findings may assist in better understanding and reducing cancer risk from DBPs in desalinated and blended water.     

The Use of Probabilistic Risk Assessment in Establishing Drinking Water Quality Objectives

There has been a trend in recent years toward the use of probabilistic methods for the analysis of uncertainty and variability in risk assessment. By developing a plausible distribution of risk, it is possible to obtain a more complete characterization of risk than is provided by either best estimates or upper limits. We describe in this paper a general framework for evaluating uncertainty and variability in risk estimation and outline how this framework can be used in the establishment of drinking water quality objectives. In addition to characterizing uncertainty and variability in risk, this framework also facilitates the identification of specific factors that contribute most to uncertainty and variability. The application of these probabilistic risk assessment methods is illustrated using tetrachloroethylene and trihalomethanes as examples.