Mechanisms of carcinogenesis by crystalline silica in relation to oxygen radicals.
The carcinogenic effects of crystalline silica in rat lungs were extensively demonstrated by many experimental long-term studies, showing a marked predominance for adenocarcinomas originating from alveolar type II cells and associated with areas of pulmonary fibrosis (silicosis). In contrast with its effects in rats, silica did not induce alveolar type II hyperplasia and lung tumors in mice and hamsters, pointing to a critical role for host factors. Using these animal models, we are investigating the role of cytokines and other cellular mediators on the proliferation of alveolar type II cells. Immunohistochemical localization of TGF-beta 1 precursor in alveolar type II cells adjacent to silicotic granulomas was shown to occur in rats, but not in mice, and hamsters, suggesting a pathogenetic role for this regulatory growth factor. Recent investigations in our laboratory on the biologic mechanisms of crystalline silica included determination of anionic sites on crystalline silica surfaces by binding of the cationic dye Janus Green B; binding of crystalline silica to DNA, demonstrated by infrared spectrometry; production of oxygen radicals by crystalline silica in aqueous media; induction of DNA strand breakage and base oxidation in vitro and its potentiation by superoxide dismutase and by hydrogen peroxide; and induction by crystalline silica of neoplastic transformation and chromosomal damage in cells in culture. On the basis of these in vitro studies, we propose that DNA binding to crystalline silica surfaces may be important in silica carcinogenesis by anchoring DNA close to sites of oxygen radical production on the silica surface, so that the oxygen radicals are produced within a few A from their target DNA nucleotides.
Saffiotti
U
U
Laboratory of Experimental Pathology, National Cancer Institute, Bethesda, Maryland 20892-0041.
Daniel
L N
LN
Mao
Y
Y
Shi
X
X
Williams
A O
AO
Kaighn
M E
ME
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D003460:Crystallization; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012822:Silicon Dioxide / Q000378:metabolism / Q000494:pharmacology*; D013499:Surface Properties
D002273:Carcinogens; D017382:Reactive Oxygen Species; D012822:Silicon Dioxide; D004247:DNA