Arsenic exposure: A public health problem leading to several cancers.

Arsenic, a metalloid and naturally occurring element, is one of the most abundant elements in the earth's crust. Water is contaminated by arsenic through natural sources (underground water, minerals and geothermal processes) and anthropogenic sources such as mining, industrial processes, and the production and use of pesticides. Humans are exposed to arsenic mainly by drinking contaminated water, and secondarily through inhalation and skin contact. Arsenic exposure is associated with the development of vascular disease, including stroke, ischemic heart disease and peripheral vascular disease. Also, arsenic increases the risk of tumors of bladder, lungs, kidneys and liver, according to the International Agency for Research on Cancer and the Food and Drug Administration. Once ingested, an estimated 70-90% of inorganic arsenic is absorbed by the gastrointestinal tract and widely distributed through the blood to different organs, primarily to the liver, kidneys, lungs and bladder and secondarily to muscle and nerve tissue. Arsenic accumulates in the organs, especially in the liver. Its excretion mostly takes place through urination. The toxicokinetics of arsenic depends on the duration of exposure, pathway of ingestion, physicochemical characteristics of the compound, and affected biological species. The present review outlines of arsenic toxic effects focusing on different cancer types whit highest prevalence's by exposure to this metalloid and signaling pathways of carcinogenesis.

Effects of arsenite on cell cycle progression in a human bladder cancer cell line.

Bladder cancer is one of the most important diseases associated with arsenic (As) exposure in view of its high prevalence and mortality rate. Experimental studies have shown that As exposure induces cell proliferation in the bladder of sodium arsenite (iAsIII) subchronically treated mice. However, there is little available information on its effects on the cell cycle of bladder cells. Thus, our purpose was to evaluate the effects of iAsIII on cell cycle progression and the response of p53 and p21 on the human-derived epithelial bladder cell line HT1197. iAsIII treatment (1-10 microM) for 24 h induced a dose-dependent increase in the proportion of cells in S-phase, which reached 65% at the highest dose. A progressive reduction in cell proliferation was also observed. BrdU was incorporated to cellular DNA in an interrupted form, suggesting an incomplete DNA synthesis. The time-course of iAsIII effects (10 microM) showed an increase in p53 protein content and a transient increase in p21 protein levels accompanying the changes in S-phase. These effects were correlated with iAs concentrations inside the cells, which were not able to metabolize inorganic arsenic. Our findings suggest that p21 was not able to block CDK2-cyclin E complex activity and was therefore unable to arrest cells in G1 allowing their progression into the S-phase. Further studies are needed to ascertain the mechanisms underlying the effects of iAsIII on the G1 to S phase transition in bladder cells.

Alteration in bilirubin excretion in individuals chronically exposed to arsenic in Mexico.

We have studied hepatic function in individuals chronically exposed to arsenic (As) via drinking water in Region Lagunera, Mexico. We studied 51 individuals living in three villages exposed to As in water. Nazareno (0.014 mgAs/l), Santa Ana (0.1 mgAs/l) and Benito Juárez (0.3 mgAs/l). We determined the serum activity of aspartate aminotransferase (SAT) and alanine aminotransferase (ALT) as indicators of hepatocellular injury and that of gamma-glutamyl-transpeptidase (GGT) and alkaline phosphatase (ALP) as indicators of cholestasic injury. Serum bilirubin was used as an indicator of organic conjugated anion transport. Total proteins, albumin and globulin fraction in serum were used as indicators of biosynthetic liver capacity. The main findings of this study were the predominantly conjugated hyperbilirubinemia and increased serum ALP activity which were related to the concentration of total arsenic (TAs) in urine, suggesting the presence of cholestasis in As-exposed individuals. No significant changes were observed in the other parameters studied.

Nuclear factor erythroid 2-related factor gene variants and susceptibility of arsenic-related skin lesions.

Inorganic arsenic (iAs) is an important pollutant associated with various chronic-degenerative diseases. The cytoprotective protein nuclear factor erythroid 2-related factor (NRF2) has been proposed as an important responsive mechanism against iAs exposure. The aim of this study was to determine whether the risk of skin lesions in people exposed to iAs-contaminated water could be modified by the presence of single nucleotide polymorphisms in the NRF2 coding gene. We studied 117 individuals with long-term iAs exposure and 120 nonexposed individuals. Total As was determined in water, meanwhile iAs and its metabolites were measured in urine. The iAs-induced skin lesion status was evaluated by expert dermatologists. We sequenced the promoter region of NRF2 in a sample of 120 healthy donors. We found four polymorphisms previously reported and one novel polymorphism in the 5' regulatory region of the NRF2. In this study, we did not find allelic and genotype association of NRF2 polymorphisms with iAs-related skin lesion. However, the analysis of haplotypes composed by -653GA, and -617CA NRF2 single nucleotide polymorphisms showed a significant association with protection against skin lesions in the low-As exposure group. This is the first report studying the association between NRF2 polymorphisms and susceptibility of As-related skin lesions. Increasing the sample size will allow us to confirm this data.

Urinary porphyrins and heme biosynthetic enzyme activities measured by HPLC in arsenic toxicity.

Arsenic can modify the urinary excretion of porphyrins in animals and humans. Arsenic also interferes with the activities of several enzymes of the heme biosynthesis pathway, such as aminolevulinate synthase (ALA-S), porphobilinogen deaminase (PBGD), uroporphyrinogen III synthase (Uro III S), uroporphyrinogen decarboxylase (URO-D), coproporphyrinogen oxidase (COPRO-O), ferrochelatase and heme oxygenase (H-O). This review deals with HPLC-based techniques for the analysis of porphyrins in human and rodent urine and several heme enzymes with discussion on their usefulness as early biomarkers of arsenic toxicity.

Altered activity of heme biosynthesis pathway enzymes in individuals chronically exposed to arsenic in Mexico.

Our objective was to evaluate the activities of some enzymes of the heme biosynthesis pathway and their relationship with the profile of urinary porphyrin excretion in individuals exposed chronically to arsenic (As) via drinking water in Region Lagunera, Mexico. We selected 17 individuals from each village studied: Benito Juarez, which has current exposure to 0.3 mg As/l; Santa Ana, where individuals have been exposed for more than 35 years to 0.4 mg As/l, but due to changes in the water supply (in 1992) exposure was reduced to its current level (0.1 mg As/l), and Nazareno, with 0.014 mg As/l. Average arsenic concentrations in urine were 2058, 398, and 88 microg As/g creatinine, respectively. The more evident alterations in heme metabolism observed in the highly exposed individuals were: (1) small but significant increases in porphobilinogen deaminase (PBG-D) and uroporphyrinogen decarboxylase (URO-D) activities in peripheral blood erythrocytes; (2) increases in the urinary excretion of total porphyrins, mainly due to coproporphyrin III (COPROIII) and uroporphyrin III (UROIII); and (3) increases in the COPRO/URO and COPROIII/COPROI ratios. No significant changes were observed in uroporphyrinogen III synthetase (UROIII-S) activity. The direct relationships between enzyme activities and urinary porphyrins, suggest that the increased porphyrin excretion was related to PBG-D, whereas the increased URO-D activity would enhance coproporphyrin synthesis and excretion at the expense of uroporphyrin. None of the human studies available have reported the marked porphyric response and enzyme inhibition observed in rodents. In conclusion, chronic As exposure alters human heme metabolism; however the severity of the effects appears to depend on characteristics of exposure not yet fully characterized.