Toxicological Sciences 59, 185-192 (2001)
Copyright © 2001 by the Society of Toxicology
Systems Toxicology |
Application of cDNA Microarray to the Study of Arsenic-Induced Liver Diseases in the Population of Guizhou, China
,1
* Guiyang Medical College Hospital, China;
Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Research Triangle Park, North Carolina;
School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina; and
§ Southwest Prefecture Endemic Prevention Station, Guizhou, China
Arsenic is an environmental toxicant and a human carcinogen. Epidemiology studies link human arsenic exposure to various diseases and cancers, including liver diseases and hepatocellular carcinoma. However, the molecular mechanisms for arsenic toxicity and carcinogenicity are poorly understood. To better understand these mechanisms, we used the human cancer cDNA expression array to profile aberrant gene expression in arsenic-exposed populations in Guizhou, China. The selected patients had a history of exposure to environmental arsenic for at least 6–10 years, and had arsenic-induced skin lesions and hepatomegaly. Samples were obtained by liver needle biopsy. Histology showed degenerative liver lesions, such as chronic inflammation, vacuolation, and focal necrosis. The University of North Carolina Hospitals provided normal human liver tissues from surgical resection or rejected transplants. Microarray was performed with total RNA from liver samples, and signal intensities were analyzed with AtlasImage software and normalized with 9 housekeeping genes. Means and SEM were calculated for statistical analysis. Approximately 60 genes (10%) were differentially expressed in arsenic-exposed human livers compared to controls. The differentially expressed genes included those involved in cell-cycle regulation, apoptosis, DNA damage response, and intermediate filaments. The observed gene alterations appear to be reflective of hepatic degenerative lesions seen in the arsenic-exposed patients. This array analysis revealed important patterns of aberrant gene expression occurring with arsenic exposure in human livers. Aberrant expressions of several genes were consistent with the results of array analysis of chronic arsenic-exposed mouse livers and chronic arsenic-transformed rat liver cells. Clearly, a variety of gene expression changes may play an integral role in arsenic hepatotoxicity and possibly carcinogenesis.
Key Words: arsenic; chronic exposure; liver degeneration; liver biopsy; aberrant gene expression; cDNA microarray.
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