Mutagenicity in Salmonella of halonitromethanes: a recently recognized class of disinfection by-products in drinking water

Kundu, Bijit; Richardson, Susan D.; Swartz, Paul; Matthews, Peggy P.; Richard, Ann M.; DeMarini, David M.

doi:10.1016/j.mrgentox.2004.05.007

Cited by 39 publications

(25 citation statements)

References 20 publications

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“…NAT1 metabolically activates aromatic and heterocyclic amines to electrophilic intermediates that initiate carcinogenesis [55,56]. The high frequency of NAT1 acetylators genotypes are important modulators of cancer susceptibility [55].…”

Section: Discussionmentioning

confidence: 99%

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Interrogating differences in expression of targeted gene sets to predict breast cancer outcome

2013

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BackgroundGenomics provides opportunities to develop precise tests for diagnostics, therapy selection and monitoring. From analyses of our studies and those of published results, 32 candidate genes were identified, whose expression appears related to clinical outcome of breast cancer. Expression of these genes was validated by qPCR and correlated with clinical follow-up to identify a gene subset for development of a prognostic test.MethodsRNA was isolated from 225 frozen invasive ductal carcinomas,and qRT-PCR was performed. Univariate hazard ratios and 95% confidence intervals for breast cancer mortality and recurrence were calculated for each of the 32 candidate genes. A multivariable gene expression model for predicting each outcome was determined using the LASSO, with 1000 splits of the data into training and testing sets to determine predictive accuracy based on the C-index. Models with gene expression data were compared to models with standard clinical covariates and models with both gene expression and clinical covariates.ResultsUnivariate analyses revealed over-expression of RABEP1, PGR, NAT1, PTP4A2, SLC39A6, ESR1, EVL, TBC1D9, FUT8, and SCUBE2 were all associated with reduced time to disease-related mortality (HR between 0.8 and 0.91, adjusted p < 0.05), while RABEP1, PGR, SLC39A6, and FUT8 were also associated with reduced recurrence times. Multivariable analyses using the LASSO revealed PGR, ESR1, NAT1, GABRP, TBC1D9, SLC39A6, and LRBA to be the most important predictors for both disease mortality and recurrence. Median C-indexes on test data sets for the gene expression, clinical, and combined models were 0.65, 0.63, and 0.65 for disease mortality and 0.64, 0.63, and 0.66 for disease recurrence, respectively.ConclusionsMolecular signatures consisting of five genes (PGR, GABRP, TBC1D9, SLC39A6 and LRBA) for disease mortality and of six genes (PGR, ESR1, GABRP, TBC1D9, SLC39A6 and LRBA) for disease recurrence were identified. These signatures were as effective as standard clinical parameters in predicting recurrence/mortality, and when combined, offered some improvement relative to clinical information alone for disease recurrence (median difference in C-values of 0.03, 95% CI of -0.08 to 0.13). Collectively, results suggest that these genes form the basis for a clinical laboratory test to predict clinical outcome of breast cancer.

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Section: Discussionmentioning

confidence: 99%

“…The high frequency of NAT1 acetylators genotypes are important modulators of cancer susceptibility [55]. Breast cancer tissues are reported to exhibit lower promoter methylation rates than normal breast, and DNA hypomethylation of the NAT1 gene plays a significant role in breast carcinogenesis [57].…”

Section: Discussionmentioning

confidence: 99%

Interrogating differences in expression of targeted gene sets to predict breast cancer outcome

2013

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“…Pegram et al (1997) and DeMarini et al (1997) demonstrated that in Salmonella transfected with rat GSTT1-1+ , brominated THMs are activated to mutagens, and they identified the specific mutagenic transitions (GC→AT) involved. Dibromonitromethane, a DBP that has not been tested for carcinogenicity, is also activated to a mutagen by a transgenic strain of Salmonella expressing GSTT1-1 (Kundu et al 2004). Authors of both in vivo and in vitro studies have suggested a model whereby brominated THMs, after dermal absorption and inhalation, escape first-pass hepatic metabolism and reach target tissues in the urinary tract where the relative proportion of GSTT1 and oxidative enzymes is more favorable for GSTT1-mediated metabolism (Landi et al 1999; Ross and Pegram 2003, 2004).…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in GSTT1 , GSTZ1 , and CYP2E1 , Disinfection By-products, and Risk of Bladder Cancer in Spain

Cantor

Villanueva

Silverman

et al. 2010

Environ Health Perspect

204

150

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BackgroundBladder cancer has been linked with long-term exposure to disinfection by-products (DBPs) in drinking water.ObjectivesIn 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.MethodsAverage 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.ResultsTHM 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 (pinteraction = 0.021), GSTZ1 rs1046428 CT/TT versus CC (pinteraction = 0.018), or CYP2E1 rs2031920 CC versus CT/TT (pinteraction = 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.ConclusionsPolymorphisms 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.

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“…This indicated that chlorination could increase the genemutation effect of drinking water. Numerous DBPs have been reported to induce the gene-mutation effects in in vitro studies [37][38][39]. In our previous study using the CHO-K1/HGPRT assay, haloacetic acids (HAAs) such as iodoacetic acid (IA), bromoacetic acid (BA), and dibromoacetic acid (DBA) were found to induce strong gene-mutation effects [25].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of genotoxic effects caused by extracts of chlorinated drinking water using a combination of three different bioassays

Zeng

Zhang

Liao

et al. 2015

Journal of Hazardous Materials

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Mutagenicity in Salmonella of halonitromethanes: a recently recognized class of disinfection by-products in drinking water

Cited by 39 publications

References 20 publications

Interrogating differences in expression of targeted gene sets to predict breast cancer outcome

Interrogating differences in expression of targeted gene sets to predict breast cancer outcome

Polymorphisms in GSTT1 , GSTZ1 , and CYP2E1 , Disinfection By-products, and Risk of Bladder Cancer in Spain

Evaluation of genotoxic effects caused by extracts of chlorinated drinking water using a combination of three different bioassays

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