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Citation
Tags
HERO ID
627205
Reference Type
Journal Article
Title
Arsenic enhancement of skin neoplasia by chronic stimulation of growth factors
Author(s)
Germolec, DR; Spalding, J; Yu, H-S; Chen, GS; Simeonova, PP; Humble, MC; Bruccoleri, A; Boorman, GA; Foley, JF; Yoshida, T; Luster, MI
Year
1998
Is Peer Reviewed?
1
Journal
American Journal of Pathology
ISSN:
0002-9440
EISSN:
1525-2191
Report Number
BIOSIS/99/00584
Volume
153
Issue
6
Page Numbers
1775-1785
Language
English
PMID
9846968
DOI
10.1016/S0002-9440(10)65692-1
Web of Science Id
WOS:000077278000014
URL
http://linkinghub.elsevier.com/retrieve/pii/S0002944010656921
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Abstract
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)-a, 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-a mRNA transcripts were found in the epidermis at clinically normal sites within 10 weeks after arsenic treatment. Immunohistochemical staining localized TGF-a 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.
Keywords
Genetics and Cytogenetics-Animal
;
Biochemical Studies-Proteins
;
Biochemical Studies-Minerals
;
Endocrine System-General
;
Integumentary System-Pathology
;
Toxicology-General
;
Neoplasms and Neoplastic Agents-Carcinogens and Carcinogenesis
;
Muridae
Tags
•
Arsenic (Inorganic)
1. Literature
PubMed
Toxline, TSCATS, & DART
Web of Science
3. Hazard ID Screening
Other potentially supporting studies
4. Adverse Outcome Pathways/Networks Screening
Relevant
•
Arsenic MOA
4. Adverse Outcome Pathways
Cell viability, cell proliferation, cell cycle changes (unrelated to regenerative proliferation)
5. Health Effect
Skin Diseases
Cancer
1. MOA Literature Screening
MOA Seeds
•
Arsenic Susceptibility
5. Health Effect
Skin Diseases
3. References Identified During Review
•
Inorganic Arsenic (7440-38-2) [Final 2025]
1. Initial Lit Search
PubMed
WOS
ToxNet
4. Considered through Oct 2015
Noncancer MOA Seeds
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