Polymorphisms in GSTT1, GSTZ1, and CYP2E1, Disinfection By-Products, and Risk of Bladder Cancer in Spain
Cantor, Kenneth P., Villanueva, Cristina M., Silverman, Debra T., Figueroa, Jonine D., Real, Francisco X., Garcia-Closas, Monserrat, Malats, Nuria, Chanock, Stephen, Yeager, Meredith, Tardon, Adonina, Garcia-Closas, Reina, Serra, Consol, Carrato, Alfredo, Castano-Vinyals, Gemma, Samanic, Claudine, Rothman, Nathaniel, Kogevinas, Manolis, Environmental Health Perspectives
BACKGROUND: Bladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water.
OBJECTIVES: In this study we investigated the combined influence of DBP exposure and polymorphisms in glutathione S-transferase (GSTT1, GSTZ1) and cytochrome P450 (CYP2E1) genes in the metabolic pathways of selected by-products on bladder cancer in a hospital-based case-control study in Spain.
METHODS: Average exposures to trihalomethanes (THMs; a surrogate for DBPs) from 15 years of age were estimated for each subject based on residential history and information on municipal water sources among 680 cases and 714 controls. We estimated effects of THMs and GSTT1, GSTZ1, and CYP2E1 polymorphisms on bladder cancer using adjusted logistic regression models with and without interaction terms.
RESULTS: THM exposure was positively associated with bladder cancer: adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.2 (0:8-1.8), 1.8 (1.1-2.9), and 1.8 (0.9-3.5) for THM quartiles 2, 3, and 4, respectively, relative to quartile 1. Associations between THMs and bladder cancer were stronger among subjects who were GSTT1 +/+ or +/- versus GSTT1 null ([p.sub.interaction] = 0.021), GSTZ1 rs 1046428 CT/TT versus CC ([p.sub.interaction] = 0.018), or CYP2E1 rs2031920 CC versus CT/TT ([p.sub.interaction] = 0.035). Among the 195 cases and 192 controls with high-risk forms of GSTT1 and GSTZ1, the ORs for quartiles 2, 3, and 4 of THMs were 1.5 (0.7-3.5), 3.4 (1.4-8.2), and 5.9 (1.8-19.0), respectively.
CONCLUSIONS: Polymorphisms in key metabolizing enzymes modified DBP-associated bladder cancer risk. The consistency of these findings with experimental observations of GSTT1, GSTZ1, and CYP2E1 activity strengthens the hypothesis that DBPs cause bladder cancer and suggests possible mechanisms as well as the classes of compounds likely to be implicated.
KEY WORDS: bladder cancer, CYP2E1, disinfection by-products, drinking water, GSTT1, GSTZ1, trihalomethanes. Environ Health Perspect 118:1545-1550 (2010). doi:10.1289/ehp.1002206 [Online 12 September 2010]
Chlorine is a cost-effective drinking water disinfectant that has been used since the early twentieth century to control a panoply of waterborne infectious diseases. By-products of the interaction of chlorine with organic precursors in water were first noted in 1974, with the discovery of trihalomethanes (THMs) in disinfected water (Bellar and Lichtenberg 1974; Rook 1974). Since then, hundreds of halogenated chemical species in the disinfection by-product (DBP) mixture have been detected, including both brominated and chlorinated compounds (Richardson 2003). THMs and haloacetic acids (HAAs) are the chemical groups at highest concentration in most by-product mixtures. Toxicological and epidemiologic studies of DBPs provide evidence of elevated risk of cancer and adverse birth outcomes (Cantor et al. 2006; Grellier et al. 2010; Nieuwenhuijsen et al. 2009). In particular, human bladder cancer has been consistently linked with long-term exposure (Cantor et al. 1998; King and Marrett 1996; McGeehin et al. 1993; Villanueva et al. 2004). These observations are supported by evidence of mutagenicity of the mixture and carcinogenicity of some constituents (Komulainen 2004; Richardson et al. 2007). To date, the role of genetic variability in modulating adverse health effects of DBPs has received limited attention (Infante-Rivard et al. 2002), and bladder cancer has not been studied in this regard.
At least three enzymes in the metabolic pathways of DBP components are candidates for examination. Glutathione S-transferase (GST) theta-1 (GSTT1) activates brominated THMs to mutagens in a transgenic strain of Salmonella (DeMarini et al. 1997; Pegram et al. 1997). GST zeta-1 (GSTZ1) catalyzes the oxygenation of dichloro- and other [alpha]-haloacids, some of which are animal carcinogens (DeAngelo et al. …