Chemistry Reference
In-Depth Information
the As-induced imbalance of DNA methylation could
disrupt normal gene expression and may have a poten-
tial role in the As-induced cellular dysfunctions and
cancer development (Zhong and Mass, 2001).
As-induced gene expression changes have been
associated with alterations in histone modifi cations and
signaling pathways. As has been shown to activate the
stress-inducible gene Hsp70 through the p38 MAPK
pathway (Thomson
et al.
, 2004). The activation of this
gene was accompanied by histone H4 acetylation and
H3 phosphorylation, whereas histone H3 remained
markedly hypoacetylated at Hsp70 chromatin (Thom-
son
et al.
, 2004). As could also upregulate protoonco-
genes
c-jun
and
c-fos
, which would require the action
of ERK. Chromatin immunoprecipitation (ChIP) assays
revealed that As treatment dramatically induced the
phosphorylation and acetylation of H3 associated with
the
c-fos
and
c-jun
genes through an ERK-dependent
pathway (Li
et al.
, 2003). In addition, it has been shown
that As induced phosphorylation of histone H3 at ser-
ine 10 in a time- and dose-dependent manner in JB6 Cl
41 cells (He
et al.
, 2003). As also dramatically increased
phosphorylation-acetylation of histone H3 at a global
level, which preceded the induction of mRNA levels
of MAPK phosphatase 1 (MKP-1). ChIP revealed that
As-induced phosphorylation-acetylation of histone H3
associated with the MKP-1 gene and enhanced the bind-
ing of RNA polymerase II to MKP-1 chromatin (Li
et al.
,
2001). MKP-1 has been shown to play a critical role in
mediating the feedback control of MAPK cascades in
a variety of cellular processes, including proliferation
and stress responsiveness. Therefore, it has been sug-
gested that As contributes to the carcinogenic process
by triggering alterations in global chromatin structure,
as well as perturbing the transcription of specifi c genes,
including
c-jun
,
c-fos
, and MKP-1 (Li
et al.
, 2001; 2003).
been linked to gene silencing. Ni exposure can also
lead to global and gene-specifi c decreases of histone
acetylation.
It has been shown that Ni inhibits the activity of
DNMTs both
in vivo
and
in vitro
(Lee
et al.
, 1998). In
cells, Ni reduced DNMTs activity and the levels of
genomic DNA methylation; however, this inhibi-
tion was transient. After a recovery period after Ni
treatment, DNMT activity rebounded slightly and
genomic DNA methylation levels increased to above
basal levels (Lee
et al.
, 1998). In Chinese hamster ovary
(CHO) cells, Ni bound selectively to heterochromatin
and caused chromosomal damage in heterochromatic
regions (Klein and Costa, 1997; Klein
et al.
, 1994a;
1994b). The binding of Ni to heterochromatin may
play a key role in Ni-induced cell transformation and
loss of senescence. Senescence in Ni-transformed cells
was restored after treatment with the DNA methyla-
tion inhibitor 5-azacytidine (5-AzaC), suggesting that
DNA hypermethylation played an important role in
the silencing of the senescence gene(s) during Ni-
induced cell transformation (Klein
et al.
, 1991). Fur-
ther studies in transgenic CHO cell lines provided
additional evidence linking Ni with DNA hypermeth-
ylation and inactivation of genes positioned near het-
erochromatin. Ni was found to silence a transgene
that was stably transfected adjacent to a heterochro-
matic region in CHO cells without causing mutations
or deletions of the transgene (Lee
et al.
, 1993). Instead,
increased DNA methylation and chromatin conden-
sation were observed at the Ni-silenced transgene
locus. The demethylating agent 5-AzaC reversed this
silencing, indicating that DNA hypermethylation was
involved in the Ni-induced transgene inactivation
(Lee
et al.
, 1995).
In addition to affecting DNA methylation, Ni has
been shown to decrease histone acetylation globally
in yeast, as well as a variety of mammalian cells
(Broday
et al.
, 2000; Kang
et al.
, 2003). ROS genera-
tion has been shown to play a role in the inhibition
of histone acetylation by Ni (Kang
et al.
, 2003). Ni
was also found to inhibit the acetylation of histones
in vitro
using purifi ed recombinant histone acetyl-
transferase (Broday
et al.
, 2000; Kang
et al.
, 2003). The
decrease of histone H4 acetylation in chromatin asso-
ciated with the Bcl-2 promoter region was verifi ed by
ChIP assays, indicating the involvement of histone
hypoacetylation in Ni-induced Bcl-2 downregulation.
This suggested that histone hypoacetylation might
play a role in Ni-induced cell apoptosis, where Bcl-2
is one of the targets (Kang
et al.
, 2004). Hypoacetyla-
tion of H4 induced by Ni was observed at lysine's 12
and 16 in the N-terminal tail of histone H4 (Broday
et al.
, 2000). Because a histidine residue is present at
5.3.2 Cd
Cadmium (Cd) exposure can result in DNA hypometh-
ylation initially, but prolonged exposure can lead to DNA
hypermethylation (Takiguchi
et al.
, 2003). In TRL1215 rat
liver cells, after 1 week of exposure to cadmium (<2.5
ยต
M
), DNMT activity and genomic DNA methylation
were reduced. However, signifi cant increases in DNMT
activity and DNA methylation were detected after 10
weeks of Cd exposure. These cells exhibited properties
of a transformed phenotype, including hyperprolif-
eration, increased invasiveness, and decreased serum
dependence (Takiguchi
et al.
, 2003).
5.3.3 Ni
Nickel (Ni) can cause global hypermethylation and
gene specifi c hypermethylation, both of which have
