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From the Environmental Immunology Laboratory,*
the
Environmental Carcinogenesis Program,
and the
Environmental Toxicology Program,¶
National
Institute of Environmental Health Sciences, National Institutes of
Health, Research Triangle Park, North Carolina; the Department of
Dermatology,
Kao-Hsiung Medical College,
Kao-Hsiung, Taiwan; the Toxicology and Molecular Biology
Branch,§
National Institute for Occupational
Safety and Health, Morgantown, West Virginia; and the Department of
Environmental Health,||
Tokai University, School of
Medicine, Kanagawa, Japan
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-Ha-ras
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.
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