Although numerous epidemiological studies have shown that inorganic arsenicals cause skin cancers and hyperkeratoses in humans , there are currently no established mechanisms for their action or animal models. Previous studies in our laboratory using primary human keratinocyte cultures demonstrated that micromolar concentrations of inorganic arsenite increased cell proliferation via the production of keratinocyte-derived growth factors. As recent reports demonstrate that overexpression of keratinocyte-derived growth factors , such as transforming growth factor (TGF)-␣, promote the formation of skin tumors , we hypothesized that similar events may be responsible for those associated with arsenic skin diseases. Thus , the influence of arsenic in humans with arsenic skin disease and on mouse skin tumor development in transgenic mice was studied. After low-dose application of tetradecanoyl phorbol acetate (TPA) , a marked increase in the number of skin papillomas occurred in Tg.AC mice , which carry the v-Haras oncogene , that received arsenic in the drinking water as compared with control drinking water, whereas no papillomas developed in arsenic-treated transgenic mice that did not receive TPA or arsenic/ TPA-treated wild-type FVB/N mice. Consistent with earlier in vitro findings , increases in granulocyte/ macrophage colony-stimulating factor (GM-CSF) and TGF-␣ mRNA transcripts were found in the epidermis at clinically normal sites within 10 weeks after arsenic treatment. Immunohistochemical staining localized TGF-␣ overexpression to the hair follicles. Injection of neutralizing antibodies to GM-CSF after TPA application reduced the number of papillomas in Tg.AC mice. Analysis of gene expression in samples of skin lesions obtained from humans chronically exposed to arsenic via their drinking water also showed similar alterations in growth factor expression. Although confirmation will be required in nontransgenic mice, these results suggest that arsenic enhances development of skin neoplasias via the chronic stimulation of keratinocyte-derived growth factors and may be a rare example of a chemical carcinogen that acts as a co-promoter. (Am J Pathol 1998, 153:1775-1785) Arsenic, a ubiquitous element, represents a human health concern when concentrated in the environment from natural or anthropogenic processes. Arsenic contamination of water supplies has resulted in a very high incidence of skin lesions and cancers in exposed populations from Taiwan, China, Eastern Europe, India, Southwestern United States, and Cental and South America. The U.S. Environmental Protection Agency (EPA) estimates that over 350,000 people in the U.S. consume drinking water containing over 50 g/L arsenic, the current EPA standard, 1 and there is significant regulatory pressure to lower the acceptable levels. Chronic exposure to inorganic arsenic in drinking water is most often associated with increased mortality from skin cancer, but recent studies have also linked arsenic exposure to neoplasias in internal organs, including the lung, liv...

In certain pathologic states, cytokine production may become spatially and temporally dysregulated, leading to their inappropriate production and potentially detrimental consequences. Tumor necrosis factor-a (TNF-a), interleukin (IL)-1, lL-6, and transforming growth factor-/I (TGF-/3) mediate a range of host responses affecting multiple cell types. To study the role of cytokines in the early stages of brain injury, we examined alterations in the 17-day-old mouse hippocampus during trimethyltin-induced neurodegeneration characterized by neuronal necrosis, microglia activation in the dentate, and astrocyte reactivity throughout the hippocampus. By 24 h after dosing, elevations in mRNA levels for TNF-a, IL-la, IL-i/I, and IL-6 mRNA were seen. TGF-~3lmRNA was elevated at 72 h. In situ hybridization showed that TNF-a and IL-la were localized to the microglia, whereas TGF-/3i was expressed predominantly in hippocampal pyramidal cells. Intercellular adhesion molecule-i, EB-22, Mac-i, and glial fibrillary acidic protein mRNA levels were elevated within the first 3 days of exposure in the absence of increased inducible nitric oxide synthetase and interferon-y mRNA. These data suggest that pro-inflammatory cytokines contribute to the progression and pattern of neuronal degeneration in the hippocampus.

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