PubMed · 5524031
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W Scheid. 1970-02-07. [Toxic polyneuritis].. https://pubmed.ncbi.nlm.nih.gov/5524031/
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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 Waste Extraction Test (WET) is used in California as a complement to the Toxicity Characteristic Leaching Procedure (TCLP). The WET protocol consists of shaking a sample with citrate buffer and determining the metal content in the solution produced. This procedure requires a 1-to-10 waste-to-liquid ratio and 48 h for extraction. Although the WET protocol proves to be very useful, it is a time-consuming step in the determination of leaching and mobility. Therefore, a microwave extraction procedure was optimized to emulate the relative extraction efficiency obtained by the WET protocol. Lead, arsenic, and copper concentrations were measured by inductively coupled plasma mass or atomic spectrometry (ICP-MS or ICP-AES), following a strict quality assurance protocol. Results obtained with this new methodology were statistically comparable to those obtained by the WET protocol. This microwave extraction approach proved simple and fast, reducing sample treatment by almost 280%. A significant reduction also occurs in waste production, materials, labor, and chemical usage. Therefore, the microwave extraction procedure is recommended as a rapid and cost effective monitoring tool for waste samples when combined with or supplemented by the traditional WET protocol.