Toxicogenomic analysis of aberrant gene expression in liver tumors and nontumorous livers of adult mice exposed in utero to inorganic arsenic

被引:60
作者
Liu, J
Xie, YX
Ward, JM
Diwan, BA
Waalkes, MP
机构
[1] NIEHS, NCI, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA
[2] NCI Frederick, Vet & Tumor Pathol Sect, Off Lab Anim Sci, Frederick, MD 21702 USA
[3] SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA
关键词
inorganic arsenic; transplacental exposure; hepatocellular carcinoma; microarray; real-time RT-PCR;
D O I
10.1093/toxsci/kfh055
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Arsenic is a known human carcinogen. We have reported that brief exposure of pregnant C3H mice to arsenite in their drinking water during gestation induced hepatocellular carcinoma (HCC) in male offspring after they became adults. Tumor formation is typically associated with multiple gene expression changes, and this study examined aberrant gene expression associated with transplacental arsenic hepatocarcinogenesis. Liver tumors and nontumorous liver samples were taken at necropsy from adult male mice exposed in utero to either 42.5 or 85 ppm arsenic as sodium arsenite or unaltered water from day 8 to 18 of gestation. Total RNA was extracted and subjected to microarray analysis. Among 600 genes, arsenic-induced HCC showed a higher rate of aberrant gene expression (>2-fold and p < 0.05, 14%) than spontaneous tumors (7.8%). Overexpression of alpha-fetoprotein, c-myc, cyclin D1, proliferation-associated protein PAG, and cytokeratin-18 were more dramatic in arsenic-induced HCC than spontaneous tumors. In nontumorous liver samples of arsenic-exposed animals, 60 genes (10%) were differentially expressed, including the increased expression of alpha-fetoprotein, c-myc, insulin-like growth factor binding protein-1, superoxide dismutase, glutathione S-transferases, and CYP2A4, and the depressed expression of CYP7B1. Real-time RT-PCR analysis largely confirmed these findings. This toxicogenomic analysis revealed several aberrant gene expression changes associated with transplacental arsenic carcinogenesis. It is indeed remarkable that expression changes occurred in adulthood even though arsenic exposure ended during gestation. Some of these aberrantly expressed genes could play a role in the development of arsenic-induced tumors, at least in the liver.
引用
收藏
页码:249 / 257
页数:9
相关论文
共 44 条
[1]   Critical windows of exposure for children's health: Cancer in human epidemiological studies and neoplasms in experimental animal models [J].
Anderson, LM ;
Diwan, BA ;
Fear, NT ;
Roman, E .
ENVIRONMENTAL HEALTH PERSPECTIVES, 2000, 108 :573-594
[2]  
[Anonymous], 1999, Arsenic in drinking water
[3]   Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma [J].
Avila, MA ;
Berasain, C ;
Torres, L ;
Martín-Duce, A ;
Corrales, FJ ;
Yang, HP ;
Prieto, J ;
Lu, SC ;
Caballería, J ;
Rodés, J ;
Mato, JM .
JOURNAL OF HEPATOLOGY, 2000, 33 (06) :907-914
[4]   Pathology related to chronic arsenic exposure [J].
Centeno, JA ;
Mullick, FG ;
Martinez, L ;
Page, NP ;
Gibb, H ;
Longfellow, D ;
Thompson, C ;
Ladich, ER .
ENVIRONMENTAL HEALTH PERSPECTIVES, 2002, 110 :883-886
[5]   Epidemiological characteristics and risk factors of hepatocellular carcinoma [J].
Chen, CJ ;
Yu, MW ;
Liaw, YF .
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 1997, 12 (9-10) :S294-S308
[6]  
Chen H, 2001, MOL CARCINOGEN, V30, P79, DOI 10.1002/1098-2744(200102)30:2<79::AID-MC1016>3.0.CO
[7]  
2-F
[8]   Exposure to inorganic arsenic metabolites during early human development [J].
Concha, G ;
Vogler, G ;
Lezcano, D ;
Nermell, B ;
Vahter, M .
TOXICOLOGICAL SCIENCES, 1998, 44 (02) :185-190
[9]  
Deane NG, 2001, CANCER RES, V61, P5389
[10]   Arsenic enhancement of skin neoplasia by chronic stimulation of growth factors [J].
Germolec, DR ;
Spalding, J ;
Yu, HS ;
Chen, GS ;
Simeonova, PP ;
Humble, MC ;
Bruccoleri, A ;
Boorman, GA ;
Foley, JF ;
Yoshida, T ;
Luster, MI .
AMERICAN JOURNAL OF PATHOLOGY, 1998, 153 (06) :1775-1785