Individual differences in arsenic metabolism and lung cancer in a case-control study in Cordoba, Argentina.

In humans, ingested inorganic arsenic is metabolized to monomethylarsenic (MMA) then to dimethylarsenic (DMA), although in most people this process is not complete. Previous studies have identified associations between the proportion of urinary MMA (%MMA) and increased risks of several arsenic-related diseases, although none of these reported on lung cancer. In this study, urinary arsenic metabolites were assessed in 45 lung cancer cases and 75 controls from arsenic-exposed areas in Cordoba, Argentina. Folate has also been linked to arsenic-disease susceptibility, thus an exploratory assessment of associations between single nucleotide polymorphisms in folate metabolizing genes, arsenic methylation, and lung cancer was also conducted. In analyses limited to subjects with metabolite concentrations above detection limits, the mean %MMA was higher in cases than in controls (17.5% versus 14.3%, p=0.01). The lung cancer odds ratio for subjects with %MMA in the upper tertile compared to those in the lowest tertile was 3.09 (95% CI, 1.08-8.81). Although the study size was too small for a definitive conclusion, there was an indication that lung cancer risks might be highest in those with a high %MMA who also carried cystathionine beta-synthase (CBS) rs234709 and rs4920037 variant alleles. This study is the first to report an association between individual differences in arsenic metabolism and lung cancer, a leading cause of arsenic-related mortality. These results add to the increasing body of evidence that variation in arsenic metabolism plays an important role in arsenic-disease susceptibility.

Bladder cancer and mate consumption in Argentina: a case-control study.

Mate is a 'tea', made from Ilex paraguariensis, widely consumed in South America, as mate con bombilla and mate cocido. Mate consumption has been associated with esophageal, oral, lung, and bladder cancers. This bladder cancer case-control study involved 114 Argentinean case-control pairs. Mate consumption was recorded for time of interview, and 20 and 40 years previously. Mate con bombilla consumed 20 years ago was associated with bladder cancer in ever-smokers (odds ratio=3.77, 95% confidence interval: 1.17-12.1), but not in never-smokers. Mate cocido was not associated with bladder cancer. These results are consistent with a previous study in Uruguay.

Genetic polymorphisms in MTHFR 677 and 1298, GSTM1 and T1, and metabolism of arsenic.

Methylation is the primary route of metabolism of inorganic arsenic in humans, and previous studies showed that interindividual differences in arsenic methylation may have important impacts on susceptibility to arsenic-induced cancer. To date, the factors that regulate arsenic methylation in humans are mostly unknown. Urinary arsenic methylation patterns and genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase (GST) were investigated in 170 subjects from an arsenic-exposed region in Argentina. Previous studies showed that subjects with the TT/AA polymorphisms at MTHFR 677 and 1298 have lower MTHFR activity than others. In this study, it was found that subjects with the TT/AA variant of MTHFR 677/1298 excreted a significantly higher proportion of ingested arsenic as inorganic arsenic and a lower proportion as dimethylarsinic acid. Women with the null genotype of GSTM1 excreted a significantly higher proportion of arsenic as monomethylarsonate than women with the active genotype. No associations were seen between polymorphisms in GSTT1 and arsenic methylation. This is the first study to report (1) associations between MTHFR and arsenic metabolism in humans, and (2) gender differences between genetic polymorphisms and urinary arsenic methylation patterns. Overall, this study provides evidence that MTHFR and GSTM1 are involved in arsenic metabolism in humans, and polymorphisms in the genes that encode these enzymes may play a role in susceptibility to arsenic-induced cancer.

Arsenic methylation and bladder cancer risk in case-control studies in Argentina and the United States.

OBJECTIVE: We sought to assess whether the metabolism of arsenic impacts a person's susceptibility to bladder cancer. METHODS: Urinary methylation products were measured in subjects from Argentina (114 cases and 114 controls) and the United States (23 cases and 49 controls). RESULTS: In Argentina, the adjusted odds ratio (OR) for subjects with a high proportion of ingested arsenic excreted as monomethylarsonate (%MMA) was 2.17 (95% confidence interval [CI] = 1.02-4.63) in smokers and 0.48 (95% CI = 0.17-1.33) in nonsmokers. In the United States, the adjusted ORs for high %MMA in subjects with arsenic intakes less than and greater than 100 microg/d were 1.20 (95% CI = 0.27-5.38) and 2.70 (95% CI = 0.39-18.6). CONCLUSIONS: Overall, these results are consistent with data from Taiwan suggesting that some individuals who excrete a higher proportion of ingested arsenic as MMA are more susceptible to arsenic-related cancer.

Arsenic-related chromosomal alterations in bladder cancer.

BACKGROUND: Previous studies have demonstrated that ingestion of arsenic in drinking water is a strong risk factor for several forms of cancer, including bladder cancer. It is not known whether arsenic-related cancers are genetically similar to cancers in unexposed individuals or what mechanisms of carcinogenesis may underlie their formation. This study was designed to compare chromosomal alterations in bladder cancers of arsenic-exposed individuals to provide insight into the mechanism of how arsenic may induce or promote cancer. METHODS: A case-case study was conducted in Argentina and Chile examining chromosomal alterations in bladder tumor DNA in 123 patients who had been exposed to arsenic in their drinking water. Patients were placed into one of four arsenic exposure categories according to their average 5-year peak arsenic exposure. Patients were also classified as ever smokers or never smokers. Comparative genomic hybridization was used to identify chromosomal alterations throughout the genome. All statistical tests were two-sided. RESULTS: The total number of chromosomal alterations was higher in individuals exposed to higher arsenic levels (5.7 +/- 5.1, 5.6 +/- 5.1, 7.3 +/- 7.4, and 9.1 +/- 6.5 [mean +/- standard deviation] chromosomal alterations per tumor with increasing arsenic exposure; P(trend) =.02, adjusted for stage and grade). The trend was stronger in high-grade (G2-G3) tumors (6.3 +/- 5.5, 8.3 +/- 4.7, 10.3 +/- 7.8, and 10.5 +/- 6.4 alterations per tumor; P(trend) =.01) than it was in low-grade (G1) tumors (3.5 +/- 3.1, 1.1 +/- 1.1, 2.5 +/- 2.5, and 3.6 +/- 3.2 alterations per tumor; P(trend) =.79). The mean number of chromosomal alterations also increased with tumor stage and grade (P(trend)<.001) independently of arsenic exposure but was not associated with smoking history. Deletion of part or all of chromosome 17p (P(trend)<.001) showed the strongest association with arsenic exposure. CONCLUSIONS: Bladder tumors in patients with higher levels of arsenic exposure showed higher levels of chromosomal instability. Most of the chromosomal alterations associated with arsenic exposure were also associated with tumor stage and grade, raising the possibility that bladder tumors from arsenic-exposed patients may behave more aggressively than tumors from unexposed patients.

Investigation of genetic polymorphisms and smoking in a bladder cancer case-control study in Argentina.

We investigated the role of glutathione S-transferase (GST) enzymes (M1, T1), methylenetetrahydrofolate (MTHFR) 677 and 1298, and the NAD(P)H:quinone oxidoreductase (NQO1) polymorphisms in a population-based bladder cancer case-control study in Argentina. Buccal cell DNA was obtained from 106 cases and 109 controls. The strongest evidence was for an interaction between NQO1 genotype and smoking. For ever smoking vs. never smoking the odds ratio was 8.6 (95% confidence interval (CI) 2.7-27), in the CC genotype, and 1.3 (95% CI 0.5-3.5) in the CT and TT genotypes combined. Also, elevated bladder cancer risks associated with GSTM1 and GSTT1 null genotypes were found in smokers. Having both null polymorphisms conferred the highest risks. The MTHFR 677 CT and TT polymorphisms appeared protective against bladder cancer.

Case-control study of bladder cancer and exposure to arsenic in Argentina.

Studies have found increased bladder cancer risks associated with high levels of arsenic in drinking water, but little information exists about risks at lower concentrations. Ecologic studies in Argentina have found increased bladder cancer mortality in Córdoba Province, where some wells are contaminated with moderate arsenic concentrations. This population-based bladder cancer case-control study in two Córdoba counties recruited 114 case-control pairs, matched on age, sex, and county, during 1996-2000. Water samples, particularly from wells, were obtained from subjects' current residences and residences in the last 40 years. Statistical analyses showed no evidence of associations with exposure estimates based on arsenic concentrations in drinking water. However, when well-water consumption per se was used as the exposure measure, time-window analyses suggested that use of well water more than 50 years before interview was associated with increased bladder cancer risk. This association was limited to ever smokers (odds ratio = 2.5, 95% confidence interval: 1.1, 5.5 for 51-70 years before interview), and the possibility that this association is due to chance cannot be excluded. This study suggests lower bladder cancer risks for arsenic than predicted from other studies but adds to evidence that the latency for arsenic-induced bladder cancers may be longer than previously thought.

P53 alterations in bladder tumors from arsenic and tobacco exposed patients.

Previous studies demonstrated that tobacco and arsenic exposure are risk factors for bladder cancer. A case-case study was conducted to compare p53 mutations in 147 bladder tumors from South American patients by tobacco and arsenic exposure. Information on residential history and lifestyle factors was collected. The prevalence of p53 mutations and protein expression was examined in relation to tumor stage, grade, patient age, gender, tobacco and arsenic exposure. Smokers were grouped as ever/never smokers and by pack years of exposure (0, 1-20, >20). Patients were also grouped into four arsenic exposure categories based on the average of the five highest years arsenic concentration in their drinking water: group 1, non-detectable to <10 microg/l (n = 50); group 2, 10-99 microg/l (n = 31); group 3, 100-299 microg/l (n = 35); group 4, >300 microg/l (n = 30). The proportion of tumor samples with p53 mutations and P53 immunopositivity increased strongly with both stage and grade, but not with arsenic exposure or smoking. The prevalence of tumors containing mutational transitions increased markedly with tumor stage (from 14 to 52%, P(trend) = 0.005) and grade (from 11 to 48%, P(trend) = 0.004) and was higher in smokers than in non-smokers (34 versus 18%, respectively, P = 0.10). An increasing trend was observed with pack years of smoking (P = 0.09). The majority of mutations in tumors from both smokers and non-smokers were G-->A transitions, however, in smokers a preference for G-->A transitions at CpG sites was observed (P = 0.07, two-tailed) and a positive trend was observed with pack years of exposure (P = 0.04). A hotspot was found at codon 273 in 12% of the tumors from smokers but was not observed in never smokers (P = 0.05) and a positive trend was observed with pack years of tobacco exposure (P = 0.001). Neither stage nor grade demonstrated a preference for CpG site mutation, suggesting that these changes may be early exposure-related events in carcinogenesis and are not related to tumor progression. Arsenic exposure was not associated with an increased prevalence of p53 mutation or P53 immunopositivity and there was no evidence of interaction between arsenic and smoking with these outcome variables.

Comprensiones en la resolución de problemas en estudiantes de Medicina: El conocimiento científico y la metodología de la investigación

Se exploran las experiencias en el tránsito formativo del tercer año de la carrera de grado, focalizándose en las comprensiones acerca de la ciencia, las formas de compresión cognitivo-emocionales acerca del conocimiento científico y sus metodologías, y los procesos de enseñanza-aprendizaje relativos a esta temática.