Arsenite and antimonite signaling pathways

Inorganic arsenic oxides have been identified as carcinogens in several human tissues, including epidermis. Human carcinogenicity of oxides of the chemically related element, antimony, is less certain. Transcriptional and proteomic profiling reveal remarkable similarities in differentially expressed genes and proteins resulting from exposure of cultured human epidermal keratinocytes to arsenite (AsIII) and antimonite (SbIII). These data were analyzed to predict downstream effects, upstream regulators and affected signaling pathways. A majority of the top findings in each category were identical after treatment with either compound. Top predicted downstream effects included categories related to cell injury, growth, survival and cancer. A major canonical pathway predicted to be affected by both arsenite and antimonite is the Nrf2-mediated oxidative stress response, while top predicted upstream regulators included oncostatin M, dexamethasone (a synthetic corticosteroid), NFE2L2 (Nrf2) and arsenite. Experimental evidence showed that oncostatin M and corticosteroids elicited several of the same transcriptional responses observed after arsenite and antimonite treatments. The striking parallels between responses to arsenite and antimonite indicate the skin carcinogenic risk of exposure to antimonite merits closer scrutiny.