Polymorphisms in XRCC1, ERCC2, and ERCC3 DNA repair genes, CYP1A1 xenobiotic metabolism gene, and tobacco are associated with bladder cancer susceptibility in Tunisian population.

Other than the established environmental risk factors associated with bladder cancer (BC), little is known about the genetic variations determining the individual susceptibility of this complex disease. This study aimed to investigate the relationship of BC with environmental agents and polymorphisms in XRCC1, ERCC2, and ERCC3 DNA repair genes and CYP1A1, CYP2D6, NAT1, and NAT2 xenobiotic metabolism genes through a hospital-based case-control study in Tunisia. The selection of the single nucleotide polymorphisms (SNPs) (rs25487, rs 13181, rs415407, rs446421, rs1058172, rs4921880, and rs1208) was performed using the dbSNP database. DNA genotyping was determined by PCR-RFLP after DNA extraction from whole blood. The risks of BC associated with every polymorphism as well as the studied environmental factors were estimated by multivariate-adjusted logistic regression using R software. In addition, gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods. Results showed that tobacco smoking and chewing parameters were significantly associated with BC risk. Single-gene variant analysis showed significant associations of the TT genotype of CYP1A1 and the rare GG genotype of ERCC2 with bladder cancer susceptibility (OR = 1.34, 95% CI 1.22-1.40, P < 0.0001). According to GMDR analysis, our findings indicated a significant association between BC and gene-gene interaction among the CYP1A1, ERCC3, and XRCC1. The present results suggest a potential role of XRCC1, ERCC2, ERCC3, and CYP1A1 besides tobacco intake in susceptibility to BC.

Cytogenetic damage in the oral mucosa cells of bladder cancer patients exposed to tobacco in Southern Tunisia.

Bladder cancer was associated to exposure to several pollutants which can be absorbed, inhaled, or possibly ingested. We analyzed the frequency of micronuclei (MNC) and binucleated cells (BNC) in exfoliated cells of the oral mucosa of 24 bladder cancer (BC) patients and 48 controls residing in Southern Tunisia. An assessment was carried out on the incidence of MNC and BNC in 1,000 cells per individual. The data were analyzed with SPSS, using the chi-square and the Mann-Whitney U test, α = 0.05. The frequency of MN cells in BC cases was 2.5-fold higher, than in the control group (P < 0.001), while the difference for BNC between both groups was not significant. The smoking habits, age, and gender significantly influenced the MN but not the BNC alterations. The results of our study showed significantly increased frequencies of MN but not of BNC in exfoliated oral cells of BC patients associated with the smoking status, sex, and age. This study provides preliminary evidence that the frequency of MN in oral mucosa could be a predictive biomarker for cancers in parts of the body other than the upper aerodigestive tract, such as BC. Further scrupulous investigations are certainly warranted in order to implement this assay as a routine test in the planning and validation of cancer surveillance and prevention programs.

Trace metal quantification in bladder biopsies from tumoral lesions of Tunisian cancer and controls subjects.

The incidence of bladder tumors has been dramatically increasing since the 1970s, possibly as a consequence of ongoing environmental pollution. Previous studies have provided some evidence of an association between cancer and exposure to carcinogenic metals. In order to examine the association between levels of toxic metals in patients with bladder tumors and controls, the amounts of arsenic, cadmium, chromium, and nickel were measured in tumoral lesions and adjacent normal part of the bladder mucosa excised for carcinoma and compared with those in the bladder mucosa of volunteer subjects operated for non-neoplastic diseases. The quantification of metals in tissue was assessed by atomic absorption spectroscopy. In tumoral tissues of the excised bladder mucosa, content of Cr and Ni was significantly low compared to that of adjacent normal tissues and control tissues while that of As and Cd in normal tissues adjacent to the tumor were significantly elevated compared to controls. Though the sample size was small, the present study shows that concentrations of metals such as Cd, Cr, As, and Ni in bladder tissue may be used as a biomarker of exposure. On the basis of the results obtained in this study, high amounts of As and Cd in adjacent normal parts of the bladders with carcinomas compared to controls would strongly suggest possible, individual or synergistic, effects of these pollutants on enzymatic systems, priming an oncogenic pathway.

Cadmium as a possible cause of bladder cancer: a review of accumulated evidence.

Bladder cancer is a significant disease, the rates of which have increased over the few last years. However, its etiology remains as yet undefined. Cadmium, a widespread environmental carcinogen that has received considerable interest, presents evidence as a possible cause of bladder cancer. A literature review was conducted from the years 1984-2013 to study the accumulated evidence for cadmium as a possible cause of bladder cancer, including routes of cadmium exposure, accumulation, toxicity, carcinogenicity, and evidence from epidemiological and experimental studies. Special reference is devoted to cadmium nephrotoxicity, which illustrates how cadmium exerts its effects on the transitional epithelium of the urinary tract. Mechanisms of carcinogenesis are discussed. The effects of cadmium on gene expression in urothelial cells exposed to cadmium are also addressed. Despite different methodologies, several epidemiologic and nephrotoxicity studies of cadmium indicate that occupational exposure to cadmium is associated with increased risk of bladder cancer and provide additional evidence that cadmium is a potential toxic element in urothelial cells. In vitro studies provide further evidence that cadmium is involved in urothelial carcinogenesis. Animal studies encounter several problems such as morphology differences between species. Among the complex mechanisms of cadmium carcinogenesis, gene expression deregulation is the subject of recent studies on bladder cadmium-induced carcinogenesis. Further research, however, will be required to promise a better understanding of the mechanisms underlying cadmium carcinogenesis and to establish the precise role of cadmium in this important malignancy.

Biomonitoring of cadmium, chromium, nickel and arsenic in general population living near mining and active industrial areas in Southern Tunisia.

The human health impact of the historic and current mining and industrial activities in Tunisia is not known. This study assessed the exposure to metals in the population of Southern Tunisia, using biomonitoring. The aim of this pilot study was to evaluate metal exposure on 350 participants living near mining and active industrial areas in the South of Tunisia. Blood specimens were analyzed for metals (Cd, Cr, As, and Ni) by Atomic Absorption Spectrometer equipped with Zeeman background correction and AS-800 auto sampler by graphite furnace and graphite tubes with integrated L'vov platform. The sample population was classified according to different age groups, sex, smoking habit, sea food and water drinking consumption, occupational exposure, amalgam fillings and place of residence. The blood As, Cd, Cr and Ni values expressed as mean ± SD were 1.56 ± 2.49, 0.74 ± 1.15, 35.04 ± 26.02 and 30.56 ± 29.96 µg/l, respectively. Blood Cd and Ni levels in smokers were 2 and 1.2 times, respectively, higher than in non-smokers. Blood Cd levels increase significantly with age (p = 0.002). As, Cd and Ni were significantly correlated with gender and age (p < 0.05). Cd level in blood samples of subjects occupationally exposed was 1.3 times higher than that of non-exposed. Blood metals were not significantly affected by amalgam fillings, place of living and sea food and drinking water consumption. This first biomonitoring study of metal exposure in the South of Tunisia reveals a substantial exposure to several metals. The pathways of exposure and health significance of these findings need to be further investigated.

Cadmium in blood of Tunisian men and risk of bladder cancer: interactions with arsenic exposure and smoking.

Prior investigations identified an association between low-level blood arsenic (As) and bladder cancer risk among Tunisian men but questions remain regarding confounding by cadmium (Cd), a well-established bladder carcinogen. A case-control study of Tunisian men was re-examined to assess the levels of cadmium in blood and reparse the association between the simultaneous exposure to these metals and bladder cancer risk. Levels of blood Cd were significantly twice higher among cases than in controls (P<0.05) and were positively correlated with smoking and age. Additionally, analysis of metal levels among non-smokers according to the region of residence showed very high blood Cd and As levels for the coastal regions of Sfax and central Tunisia. After controlling for potential confounders, for low blood As levels (<0.67 µg/L), the OR for blood Cd was 4.10 (95 % CI 1.64-10.81), while for higher levels (>0.67 µg/L), it was reduced to 2.10 (CI, 1.06-4.17). Adjustment for Cd exposure did not alter the risk associated to As exposure. This study is the first to report the relationship between Cd exposure and risk of bladder cancer occurrence in interaction with smoking and As exposure. Smoking is shown to be the main exposure source to Cd in the Tunisian population but also environmental pollution seems to be responsible of Cd exposure among non-smokers. Exposure assessment studies encompassing a wider population are needed.

Blood nickel and chromium levels in association with smoking and occupational exposure among head and neck cancer patients in Tunisia.

Chronic exposure to chromium (Cr) and nickel (Ni) has long been recognized as being capable to increase head and neck cancer (HNC) incidence among exposed human populations. This study represents the first biomonitoring of Cr and Ni exposure in Tunisia and focuses on a possible association with HNC risk. The aim of the present study was to evaluate the concentrations of Cr and Ni in the blood of HNC patients and controls. Metals blood levels of 169 HNC patients and 351 controls were determined using a Perkin-Elmer Analyst 800 Atomic Absorption Spectrometer. Mean blood levels of Cr and Ni in HNC cases (52.15 and 111.60 µg/L, respectively) were significantly higher than those of controls (37.04 and 30.50 µg/L, respectively). Cases' blood levels of Cr and Ni were significantly higher than those of controls after controlling for the other risk factors of HNC, including smoking, shisha consumption, occupational exposure, and nearby environment (P<0.05). Among these risk factors, smoking and occupational exposure presented the most significant association with HNC (odds ratio (OR)=6.54 and 7.66, respectively, P<0.001). Cr and Ni levels in blood sample of cases and controls that are smoker/occupationally exposed were higher than that of non-smoker/non-occupationally exposed (P<0.05). Smokers who are occupationally exposed present the most significant association with HNC (OR=25.08, P<0.0001). High levels of blood Cr (OR=2.09) and high levels of blood Ni (OR=8.87) were strongly associated with HNC after other potential confounders were controlled (P=0.004 and P<0.0001, respectively). This study suggested a potential role of Cr and Ni in the mechanism of HNC development.

Low-level arsenic exposure is associated with bladder cancer risk and cigarette smoking: a case-control study among men in Tunisia.

Although exposure to high levels of arsenic is associated with excess bladder cancer risk, lower exposures generally are not. This study represents the first biomonitoring of arsenic exposure in Tunisia and focuses on a possible association with bladder cancer risk. In this context, 124 male bladder cancer cases and 220 controls were recruited and blood samples were analyzed to determine the concentration of As. The study subjects were stratified into median groups based on concentrations of arsenic in their blood. Blood arsenic (B-As) was significantly two to threefold higher in bladder cancer cases than in controls (p<0.05). The arsenic concentrations were significantly higher among both smokers and workers in construction. However, neither drinking water nor seafood was found to be incriminated as exposure sources. The adjusted risk ratios for B-As concentration categories 0.1-0.67 and ≥ 0.67 µg/L were 0.18 (95% CI=0.014-2.95) and 2.44 (95% CI=1.11-5.35), respectively. Arsenic levels were not found to be associated with tumor grade or stage. The considerable risk in the category of highest cumulative exposure argues for an association between bladder cancer risk and low-level arsenic exposure. Future investigations with larger samples and using techniques that allow the distinction of the different arsenic species should better elucidate this association. Furthermore, the modulation of arsenic level according to the histological grade may be of potential to be used as a diagnostic marker of the disease process and its possible relationship etiologically.