Nickel - Toxicology of Metals - page 737

involved in nickel's activation of HIF-1-dependent
genes (Salnikow et al ., 2002). When Affymetrix gene
chips were used to study nickel treated (1 mmol/L
NiCl 2 , 24 hours) HIF-1

et al ., 2003). Nickel induced NF- B activity and adhe-

sion molecule expression were found to be inhibited
by the antioxidant pyrrolidine dithiocarbamate, indi-
cating some involvement of redox-dependent mecha-
nisms by high doses of nickel (Goebeler, 1995). Nickel
subsulfi de-induced ROS have also been implicated in
activation of AP-1and IL-8 in human bronchial epithe-
lial Beas-2B cells at relevant nickel doses of 1.17

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competent versus knockout
cells, numerous genes were found to be up- or down-
regulated in a HIF-dependent manner (Davidson et al .,
2003; 2004; Salnikow et al ., 2003a, b). This dose of nickel
chloride is nontoxic, yielding approximately 90% sur-
vival of human A549 lung cells. Some examples of
these nickel-induced genes include 1, 4-alpha-glucan
branching enzyme 1 (GBE1) and Bcl-2-binding protein
Nip3 (BNIP3). Serpina3g, a member of the mouse ser-
pin family, was downregulated by nickel by means
of HIF-1

α

g/
cm2 Ni 3 S 2 (Barchowsky, 2002). At relevant nickel
doses, the generation of hydrogen peroxide H 2 O 2
by nickel (1 mmol/L NiCl 2 or 2

µ

g/cm2 Ni 3 S 2 , 6-48
hours) was also reported to be involved in NFAT acti-
vation (Huang et al ., 2001). In contrast, pretreatment
of cells with sodium formate (an OH radical scaven-
ger) or superoxide dismutase (an O 2 .− radical scaven-
ger) did not show any inhibitory effects (Huang et al .,
2001). Related to infl ammation associated with nickel-
induced contact dermatitis, involvement of MAPK,
JNK, and ERK pathways has been demonstrated in
skin dendritic cells exposed to NiSO 4 (500

µ

dependent pathways, as was asparaginyl
hydroxylase FIH-1 and acetyltransferase ARD-1 in
A549 cells (Salnikow et al ., 2003a). Although the exact
mechanism for HIF-1 activation by Ni is not yet con-
fi rmed, several hypotheses have been proposed. These
include the ability of nickel to stabilize HIF-1

α

protein
by inhibiting the posttranslational modifi cations of
HIF-1

α

mol/L, 24
hours) to simulate contact exposure (Boislève et al .,
2005).

µ

; the impairment of prolyl hydroxylase activities
by cellular iron depletion caused by nickel competition
for the DMT-1 transporter, as well as by substitution of
nickel for iron in the Hif-prolyl hydroxylase (Davidson
et al ., 2004).
Several other studies have identifi ed genes whose
expression is altered after nickel treatment of cells
or organisms. By use of random, arbitrarily primed-
polymerase chain reaction (RAP-PCR) mRNA differential
display, Verma et al . (2004) identifi ed several genes that
were differentially expressed between nontransformed
and insoluble nickel-transformed C3H10T1/2-derived
mouse embryo cell lines. The calnexin gene (encod-
ing a type I membrane protein/molecular chaperone),
ect-2 proto-oncogene, and Wdr1 stress-inducible gene
were up-regulated, whereas DRIP/TRAP-80 (vitamin
D-interacting protein/thyroid hormone activating pro-
tein 80) gene, IGFR1 (insulin-like growth factor receptor
1), and SNAP (small nuclear activating protein C3) were
down-regulated in the nickel-transformed cell lines.
Nickel activation of NF-

α

10 EPIGENETIC EFFECTS

10.1 Effects on DNA Methylation
and Epigenetic Silencing
Because carcinogenic nickel compounds were not
found to be mutagenic, alternative mechanisms for
their carcinogenic effects were sought. In a seminal
paper published in 1991 (Klein et al ., 1991), carcino-
genic nickel compounds were found to induce DNA
methylation and silence tumor suppressor/senes-
cence genes located on the mammalian X chromo-
some. More recent studies have suggested that the
ETS transcription factor MEF may be the tumor
suppressor gene that was epigenetically silenced by
nickel on the X chromosome (Seki et al ., 2002). Further
studies showed that nickel-induced silencing exhib-
ited positional effects both in mammalian cells and
in yeast. For example, in yeast cells nickel silenced an
Ura A gene when it was placed 1.7 kb from a telomere
silencing element but not when it was 2.0 kb (Broday
et al ., 1999a). Similarly, in a mammalian transgenic
system, nickel silenced the G12 transgenic cell line
because of the position of the transgene on chromo-
some 1 near the telomere and near heterochromatin,
whereas it could not silence the G10 cell line where an
identical construct was placed on chromosome 6 but
not near any heterochromatin (Broday et al ., 1999b).
A model was proposed for these effects involving
the ability of nickel ions to bind to the phosphate

B activity and DNA bind-
ing have been reported in several studies (Aiba et al .,
2003; Goebler et al ., 1995), leading to the subsequent
transcription of infl ammatory cytokines (IL-6) and
adhesion molecules such as ICAM-1, VCAM-1, and
E-selectin. However high nickel doses (400 mmol/
L NaCl 2 ) were often used in older studies (Goebeler
et al ., 1995). At relevant low doses, nickel chloride
(0.25-0.5 mmol/L)-induced activation of HIF-1

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also
leads to the expression of the Cap43, a protein that
may have utility as a potential biomarker of nickel
exposure but has also been recently identifi ed to be
the same as NDRG1, a protein involved in a demy-
elinating neurodegenerative disease gene (Salnikow

α