Arsenic Enhancement of Skin Neoplasia by Chronic Stimulation of Growth Factors

Details

• Personal Author:
  Boorman GA ; Bruccoleri A ; Chen GS ; Foley JF ; Germolec DR ; Humble MC ; Luster MI ; Simeonova PP ; Spalding J ; Yoshida T ; Yu H
• Description:
  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)-alpha, 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-alpha mRNA transcripts were found in the epidermis at clinically normal sites within 10 weeks after arsenic treatment. Immunohistochemical staining localized TGF-alpha 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. [Description provided by NIOSH]
• Subjects:
  Animals Arsenic Epidemiology Inorganic Chemicals Laboratories Neoplasms Occupational Health Safety Skin Skin Diseases
• Keywords:
  Animal-studies Arsenates Arsenic-compounds Cancer Laboratory-animals Models Skin-cancer Skin-diseases Skin-tumors
• ISSN:
  0002-9440
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  North Carolina ; OSHA Region 3 ; OSHA Region 4 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  153
• Issue:
  6
• NIOSHTIC Number:
  nn:20024269
• Citation:
  Am J Pathol 1998 Dec; 153(6):1775-1785
• Contact Point Address:
  Dr. Dori R. Germolec, Environmental Immunology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, Research Triangle Park, NC 27709
• Email:
  germolec@niehs.nih.gov
• CAS Registry Number:
  Arsenic (CAS RN 7440-38-2)
• Federal Fiscal Year:
  1999
• Peer Reviewed:
  True
• Source Full Name:
  The American Journal of Pathology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:ad71917d63841384358229d675181372355b3db0f52e3202456727ee2178c4d381fb0c99cf1a78b7bfec5c566ebfe4b286280657d5308f3f313b9db4cd1a7522
• Download URL:
  https://stacks.cdc.gov/view/cdc/196157/cdc_196157_DS1.pdf
• File Type:
  [PDF - 1.32 MB ]