Arsenic is known to target the liver in humans and its exposure can
cause development liver lesions, fatty infilteration and hepato-cellular
carcinomas. hepato-cellular lesions including neoplasia was reported in mice
after repeated injections of Arsenate in mice. In addition exposure in organic
arsenic to pregnant mice showed high occurance of hepatocellular carcinomas in
adult offsprings. Therefore we can say Arsenic has the potential to induce
liver carcinogenesis in both human and non human species.
(5). (6). (7). (8).
In liver, the methylation of Arsenic by an incompletely characterized
methyl transferase using S adenosyl methionine (SAM) as a methyl donor to MMA
and DMA occurs at a high level in mammals. This can lead to depletion of SAM in
normal cellular reactions.
Hydroxyl molecules are
reported to form ring structures
with phenylarsine oxide in the gaseous phase.
(12,13). (12,14). SAM is a global
methyl donor, required for DNA methylations and its depletion can lead to
hypomethylation of DNA resulting in alteration of gene expression like c myc, c
met, cyclin D1 and induction of carcinogenesis. (15). (9). (16–18). The DNA
hypomethylation. (10,11).Because the liver is a target of arsenic
carcinogenesis inhumans and rodents (2,8), and altered DNA methylation hasbeen
associated with arsenic-induced malignant transformationand aberrant gene
expression in rodent liver cells (9–11),the present study was designed to
investigate genome-wideand site-specific DNA methylation status in mouse liver
afterchronic oral inorganic arsenic exposure. In addition, cDNAmicroarray
techniques were used to profile gene expressionchanges. Critical expression
changes were confirmed byRT–PCR at the transcriptional level and by
immunohistochemicalanalysis at the translation level. The results indicatethat
arsenic induces global DNA hypomethylation and aberrantgene expression in vivo,
as well as the specific hypomethylationof the ER-a promoter region. All these
factorscould play a potential role in arsenic hepatocarcinogenesis.
The present study demonstrates clearly that chronic oral
inorganicarsenic exposure can produce global DNA hypomethylationin the mouse
liver and specific hypomethylation of thepromoter region of the ER-a gene. This
is consistent with ourprior in vitro work showing genome-wide
hypomethylationand concurrent aberrant gene expression in liver cells
malignantlytransformed by arsenic (9,10). Alteration of hepaticgene expression
was also evident in the present study, andsome, but not all of these may be a
result of alteration inDNA methylation status. For instance, loss of promoter
regionmethylation is associated with increased expression of ER-a(26,27).
RT–PCR and immunohistology analysis confirmedthe over-expression of ER-a and
cyclin D1 at the mRNA andthe protein levels. Although tumors did not develop in
the miceexposed to arsenic in the present study, cellular hypertrophyand
steatosis were common. Steatosis is associated with consumptionof
methyl-deficient diets that can lead to liver tumorformation (28,29). Thus,
alterations in DNA methylation statustogether with the aberrant gene expression
patterns observed inthe present work may provide novel insight into the
mechanismsof arsenic hepatocarcinogenesis.Methylation of DNA is an epigenetic
modification that canplay an important role in the control of gene expression
inmammalian cells, and aberrant methylation frequently occursduring oncogenesis
(15,30,31). In vertebrate DNA, ~3–5% ofthe total cytosine residues are present
as 5 mdC (15,24,32).