In the present work, microarray analysis showed alterations in expression of _5% of the genes investigated including steroid-related genes, cytokines, apoptosis genes and cell cycle-related genes. Especially noteworthy are the overexpression of ER-a gene and cyclin D1. Prior work has shown that chronic exposure to inorganic arsenic in mice can produce hepatocellular proliferative lesions together with over-expression of the ER-a and cyclin D1 (7). In mice, transplacental arsenic exposure, which produces hepatocellular carcinoma when animals reach adulthood, also causes overexpression of ER-a and cyclin D1 (42).

ER-a, a member of the steroid hormone receptor superfamily, is a hormoneactivated transcription factor that mediates the biological effects of estrogen in a variety of responsive tissues (43). The expression of ER-a can be affected by changes in methylation of the ER gene (26,27,44), and is often over-expressed in early proliferative lesions in the liver or elsewhere (45–47).¬†Estrogens are unequivocal liver carcinogens in rodents and suspected human carcinogens (48). It has been proposed that they act as epigenetic carcinogens probably via ER-mediated mechanisms (22,45,48). There is strong evidence that aberrant mitogenesis and hepatocellular proliferation observed during estrogen-induced hepatocarcinogenesis is mediated through ER (48).

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We have reported that over-expression of the ER-a from arsenic exposure is associated with proliferative lesions and hepatocellular carcinogenesis (7,8,42) and this overexpression is associated marked loss of methylation in the ER-a promoter region (42). In human hepatocellular carcinoma recent evidence indicates that in ~37% of cases the ER gene appears to be hypomethylated (49). Thus, the overexpression of ER-a observed in the present study in the mouse liver after chronic arsenic exposure supports a hypothesis that arsenic might somehow act through an estrogenic mechanism.

Presumably, the over-expressed ER-a would create hepatic hypersensitivity to endogenous steroids. Microarray analysis also revealed arsenic-induced overexpression of the cell cycle regulating genes cyclin D1, cyclin D2 and cyclin D3. Cyclin D1, an important cell-cycle regulating oncogene (23), is transcriptionally up-regulated by numerous growth factors, including potentially estrogens (50). Cyclin D1 is also over-expressed in liver cells malignantly transformed with arsenic (11) and is considered a hepatic oncogene (51). Targeted over-expression of cyclin D1 in the liver is alone sufficient to initiate hepatocellular carcinogenesis (51), indicating it is a cause, and not a consequence, of malignant transformation of liver cells.

In addition, co-overexpression of cyclin D1 and ER-a has been reported after chronic arsenic exposure (7,42), especially in estrogen responsive tissues where arsenic-induced proliferative lesions and cancers occur, such as the uterus and liver (7,8,42,52). Aberrant expression of cyclin D1 would also be expected to cooperate with other oncogenes in carcinogenic transformation (23). In the present study, the 16 CpG sites in promoter region of cyclin D1 gene from control liver were essentially unmethylated, and thus no significant arsenic-induced changes occurred in cyclin D1 methylation. Since cyclin D1 is potentially an ER-a-linked gene, the activation of cyclin D1 by arsenic in this case may occur secondarily to ER-a over-expression. In any event, overexpression of cyclin D1 has been observed after arsenic exposure in a number of both in vitro (10,11,53,54) and in vivo (7,41,55,56) model systems of arsenic carcinogenesis, including skin and bladder cancers in rodents associated with arsenic exposure.

Thus, it appears cyclin D1 over-expression may be a consistent event in arsenic carcinogenesis. Although at one time, arsenic was thought to be an equivocal carcinogen, that was clearly carcinogenic in humans but not active in rodents, there is accumulating evidence that arsenicals can be carcinogenic in animals (8,52,55,56,57). Indeed, animal models of arsenic carcinogenesis have been developed that show activity in skin, urinary bladder, liver and lung (8,52,55,56,57), all of which are known human target tissues (2).

This target-site concordance provides support to the concept that similar carcinogenic mechanisms may apply in humans and rodents. 


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