PubMed · 13080190
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G A JOHNSON. 1953. An arsine problem: engineering notes.. https://doi.org/10.1080/00968205309343934
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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.
The aim of this study was to examine the bioaccessibility (maximum soluble concentration in gastrointestinal medium) of total (AsT) and inorganic (AsI) arsenic contents and the effect on them of cooking edible seaweed, a food of great interest because of its high As content. An in vitro gastrointestinal digestion (pepsin, pH 2, and pancreatin-bile extract, pH 7) was applied to obtain the mineral soluble fraction of three seaweeds (Hizikia fusiforme, Porphyra sp., and Enteromorpha sp.). AsT was determined by dry-ashing flow injection hydride generation atomic absorption spectrometry. AsI was determined by acid digestion, solvent extraction, and flow injection hydride generation atomic absorption spectrometry. The bioaccessibility of AsI increased significantly after cooking, attaining 73% in Porphyra sp. and 88% in H. fusiforme. For cooked H. fusiforme, the AsI attained in the bioaccessible fraction was 26 microg g(-1) seaweed, a concentration that is a warning of the toxicological risk of this food.
Normal human epidermal keratinocytes (NHEK) have been chosen as an in vitro model to test the hypothesis that chemicals which alter or interfere in cellular differentiation will concomitantly induce growth perturbations and are, thus, potential carcinogens. In these studies, we have focused on two known skin carcinogens, arsenic and benzo(a)pyrene (BaP). Our results demonstrated that BaP inhibits terminal differentiation in NHEK, as measured by cross-linked envelope (CLE) formation, up to 5.8-fold in control and 1.7-fold in calcium (Ca2+)-treated cells. In comparison, arsenic decreased CLE formation 20-fold in control cells and 5.5-fold in Ca2+-treated NHEK. To characterize the effects of these agents on the growth rate and cell cycle distributions of NHEK, flow cytometric analysis was used. BaP at 2 microM increased proliferation rates by 29%. Altered cell-cycle distribution in BaP-treated cells indicated a more rapid progression through the cell cycle, possibly by a shortened G2 phase. In contrast, arsenic at 5 microM inhibited proliferation by 25%; growth arrest (9%) was also observed in NHEK treated with 2 mM Ca2+. Our findings suggest that, although both BaP and arsenic inhibit CLE production in NHEK, different mechanisms may be involved. Studies in progress will attempt to identify molecular markers involved in the observed chemical effects. These markers will facilitate a mechanistic understanding of how an altered balance between growth and differentiation may play a role in the transformation process in NHEK.