Understanding arsenic carcinogenicity by the use of animal models.
Although numerous epidemiological studies have indicated that human arsenic exposure is associated with increased incidences of bladder, liver, skin, and lung cancers, limited attempts have been made to understand mechanisms of carcinogenicity using animal models. Dimethylarsinic acid (DMA), an organic arsenic compound, is a major metabolite of ingested inorganic arsenics in mammals. Recent in vitro studies have proven DMA to be a potent clastogenic agent, capable of inducing DNA damage including double strand breaks and cross-link formation. In our attempts to clarify DMA carcinogenicity, we have recently shown carcinogenic effects of DMA and its related metabolites using various experimental protocols in rats and mice: (1) a multi-organ promotion bioassay in rats; (2) a two-stage promotion bioassay by DMA of rat urinary bladder and liver carcinogenesis; (3) a 2-year carcinogenicity test of DMA in rats; (4) studies on the effects of DMA on lung carcinogenesis in rats; (5) promotion of skin carcinogenesis by DMA in keratin (K6)/ornithine decarboxylase (ODC) transgenic mice; (6) carcinogenicity of DMA in p53(+/-) knockout and Mmh/8-OXOG-DNA glycolase (OGG1) mutant mice; (7) promoting effects of DMA and related organic arsenicals in rat liver; (8) promoting effects of DMA and related organic arsenicals in a rat multi-organ carcinogenesis test; and (9) 2-year carcinogenicity tests of monomethylarsonic acid (MMA) and trimethylarsine oxide (TMAO) in rats. The results revealed that the adverse effects of arsenic occurred either by promoting and initiating carcinogenesis. These data, as covered in the present review, suggest that several mechanisms may be involved in arsenic carcinogenesis.
Department of Pathology, Osaka City University Medical School, Osaka 545-8585, Japan. wani@med.osaka-cu.ac.jp
Hideki
H
Wanibuchi
Elsayed I
EI
Salim
Anna
A
Kinoshita
Jun
J
Shen
Min
M
Wei
Keiichirou
K
Morimura
Kaoru
K
Yoshida
Koichi
K
Kuroda
Ginji
G
Endo
Shoji
S
Fukushima
D000818:Animals; D020261:Arsenic Poisoning / Q000378:metabolism*; D002273:Carcinogens; D004195:Disease Models, Animal; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced*
D002273:Carcinogens