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PMID: 15345372 Published · ppublish English Journal Article

Biokinetics and subchronic toxic effects of oral arsenite, arsenate, monomethylarsonic acid, and dimethylarsinic acid in v-Ha-ras transgenic (Tg.AC) mice.

Environmental health perspectives ·Vol. 112 ·No. 12 ·2004-08-00 ·Pages 1255-63

Xie Y, Trouba KJ, Liu J, Waalkes MP, Germolec DR

Abstract

Previous research demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment increased the number of skin papillomas in v-Ha-ras transgenic (Tg.AC) mice that had received sodium arsenite [(As(III)] in drinking water, indicating that this model is useful for studying the toxic effects of arsenic in vivo. Because the liver is a known target of arsenic, we examined the pathophysiologic and molecular effects of inorganic and organic arsenical exposure on Tg.AC mouse liver in this study. Tg.AC mice were provided drinking water containing As(III), sodium arsenate [As(V)], monomethylarsonic acid [(MMA(V)], and 1,000 ppm dimethylarsinic acid [DMA(V)] at dosages of 150, 200, 1,500, or 1,000 ppm as arsenic, respectively, for 17 weeks. Control mice received unaltered water. Four weeks after initiation of arsenic treatment, TPA at a dose of 1.25 microg/200 microL acetone was applied twice a week for 2 weeks to the shaved dorsal skin of all mice, including the controls not receiving arsenic. In some cases arsenic exposure reduced body weight gain and caused mortality (including moribundity). Arsenical exposure resulted in a dose-dependent accumulation of arsenic in the liver that was unexpectedly independent of chemical species and produced hepatic global DNA hypomethylation. cDNA microarray and reverse transcriptase-polymerase chain reaction analysis revealed that all arsenicals altered the expression of numerous genes associated with toxicity and cancer. However, organic arsenicals [MMA(V) and DMA(V)] induced a pattern of gene expression dissimilar to that of inorganic arsenicals. In summary, subchronic exposure of Tg.AC mice to inorganic or organic arsenicals resulted in toxic manifestations, hepatic arsenic accumulation, global DNA hypomethylation, and numerous gene expression changes. These effects may play a role in arsenic-induced hepatotoxicity and carcinogenesis and may be of particular toxicologic relevance.

MeSH Terms
Administration, Oral Animals Arsenates/administration & dosage,pharmacokinetics,toxicity Arsenicals/administration & dosage,adverse effects,pharmacokinetics Arsenites/administration & dosage,pharmacokinetics,toxicity Cacodylic Acid/administration & dosage,pharmacokinetics,toxicity DNA Methylation Gene Expression Profiling Herbicides/administration & dosage,pharmacokinetics,toxicity Kinetics Liver/drug effects,pathology Mice Mice, Transgenic Oligonucleotide Array Sequence Analysis Toxicogenetics/methods Water Supply
Chemicals
Arsenates Arsenicals Arsenites Herbicides Cacodylic Acid monomethylarsonic acid arsenite arsenic acid
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Xie Yaxiong
Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences Research Triangle Park, North Carolina 27709, USA.
Trouba Kevin J
Liu Jie
Waalkes Michael P
Germolec Dori R
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Article Info
Journal
Environmental health perspectives
Abbr.
Environ Health Perspect
ISSN
0091-6765
DOI
10.1289/txg.7152
Published
2004-08-00
Pages
1255-63
Language
English
Region
United States
NLM ID
0330411
PMCID
PMC1277119
Subset
IM
External Links
PubMed source DOI: 10.1289/txg.7152 PMC Full Text View journal details
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