PubMed · 7935832
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D Ahmann, A L Roberts, L R Krumholz, F M Morel. 1994-10-27. Microbe grows by reducing arsenic.. https://doi.org/10.1038/371750a0
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Chronic inorganic arsenic (iAs) exposure affects > 220 million people worldwide and skin cancer is a hallmark of long-term iAs exposure. Limited information exists regarding arsenic methylation by human keratinocytes and how methylation influences skin carcinogenesis. Inorganic arsenite (iAsIII) and its methylated metabolites disrupt diverse zinc finger proteins, leading to differential toxicity patterns. We examined arsenic methylation capacity in non-malignant human keratinocytes and interrogated proteomic remodeling across three stages of iAsIII induced malignant transformation using the well-established preclinical HaCaT model. Arsenic methylation was assessed by hydride generation cryotrapping inductively coupled-mass spectrometry and global proteomic changes were analyzed by tandem-mass tagging liquid chromatography-tandem mass spectrometry. Primary, hTERT-immortalized and HaCaT human keratinocytes exhibited negligible arsenic methylation, with iAsIII comprising at least 98.5% of total intracellular arsenic, attributable to minimal expression of arsenite methyltransferase. Proteomic profiling identified over 275 differentially expressed proteins at each stage of transformation, including multiple zinc finger proteins implicated in cell cycle control, RNA metabolism, and genome stability. Ingenuity® Pathway Analysis revealed progressive, coordinated disruption of cancer-associated pathways and regulatory networks over the transformation timeline, including zinc-coordinating upstream regulators that may explain widespread pathway dysregulation. Collectively, our findings suggest that iAsIII promotes skin carcinogenesis by disrupting C3H1- and C4-type zinc finger protein-centered regulatory networks that coordinate cancer-associated signaling and metabolic pathways in human keratinocytes, highlighting key candidates for future mechanistic studies.
Arsenic (As) is a common element in the environment with many industrial uses, but it also can be a contaminant in drinking water and present serious health concerns. Earlier studies on the quality of drinking water in the city of Hermosillo, Sonora, México, showed high levels of As (> 0.05 ppm) in water from wells located in the northern part of the city. Additionally a high positive correlation between the levels of Fluoride (F) and As in the same wells was found. Therefore, the objective of this study was to determine the excretion of As in children, 7-11 years of age, that had been exposed to elevated levels of As in their drinking water. Twenty-four-hour urine samples and a water sample taken directly in the home were collected from school age children living in two different areas with known high levels of As in their drinking water. A control group with normal levels of As in their water was also included. As was determined by an atomic absorption-hydride generator, verified with the use of NBS certified standards (SRM 1643a and SRM 2670). None of the water samples exceeded the limit established for drinking water; however, there was a significant difference between the intake of As and the As in drinking water among the three areas of the study. Average As in water was 0.009 +/- 0.002 and 0.030 +/- 0.011 micrograms/ml between the control and high areas. Intake (in micrograms/day) was 15 +/- 3 and 54 +/- 18. In the group consuming water with high levels of As, 65% of the children exceeded the recommended dose of < 1 micrograms/kg/day (EPA, 1988). Several children in this study also had high levels of As in their urine. Even though As levels in the drinking water are within the norms, it appears that children exposed to high levels of As in their drinking water may have a health risk.
OBJECT: The dose-response relationship for lung carcinoma and other cancers at low doses of As is highly uncertain because it is based on modeling data collected in populations with a high daily intake of the element. The finding of a slightly increased exposure to arsenic in certain groups of the Belgian general population prompted us to examine whether this had repercussions on the causes of mortality. METHOD: Statistics of mortality by causes with a possible link to exposure to the element (standardized mortality ratio) were analyzed in groups of the Belgian population previously shown to have been exposed to As from natural (drinking water) and/or industrial (nonferrous metal smelter emissions) sources. RESULTS: A moderately increased absorption of As, leading to a 3- to 4- fold higher urinary excretion (35 micrograms/day as compared with 6-10 micrograms As/day in nonexposed subjects) did not enhance the mortality by diseases of the nervous system, liver and heart, and cancers. An increase in mortality by lung cancer, however, was observed in men but not women living around zinc smelters and might be related to past occupational exposure and/or smoking habits. CONCLUSION: A low to moderate level of environmental exposure to inorganic arsenic (0.3 microgram As/m3 of air; 20-50 micrograms As/l of drinking water) does not seem to affect the causes of mortality, suggesting in particular nonlinearity of the dose-response relationship for arsenic and cancer.