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RRJoT (2016) 1-10 © STM Journals 2016. All Rights Reserved Page 1
Research & Reviews: A Journal of Toxicology
ISSN: 2231-3834(online), ISSN: 2349-1264(print)
Volume 6, Issue 1
www.stmjournals.com
Cadmium and Apoptosis: A Molecular Approach
K. Shagirtha1 and S. Miltonprabu2*
1Department of Biochemistry, St. Joseph’s College, Cuddalore, Tamilnadu, India
2Department of Zoology, Annamalai University, Annamalainagar, Tamilnadu, India
Abstract
Apoptosis, also known as programmed cell death is a highly regulated and fundamental
process found in all multicellular organisms. It is not only implicated in regulatory
mechanisms of cells, but has been attributed to a number of diseases, like inflammation,
malignancy, autoimmunity and neuro degeneration. A variability of pollutants can persuade
apoptosis. Oncogenic transition metals like cadmium, promote apoptosis alongside DNA base
modifications, strand breaks and rearrangements. Generation of reactive oxygen species,
accumulation of Ca2+, upregulation of caspase-3, downregulation of bcl-2,and deficiency of p-
53 lead to the Cadmium (Cd) induced apoptosis. Metallothionein expression determines the
choice between apoptosis and necrosis in Cd induced toxicity. Thus, disorders of apoptosis
may play a critical role in some of the most debilitating metal-induced afflictions including
hepato toxicity, renal toxicity, neuro toxicity, autoimmunity and carcinogenesis. An
understanding of Cd-induced apoptosis will be obliging in the development of precautionary
molecular approach.
Keywords: Metals, cadmium, apoptosis, cell-proliferation, carcinogenicity
*Author of correspondence E-mail: smprabu73@gmail.com
INTRODUCTION
Metals have been exploited by man since
antiquity. Anthropogenic uses have led to a
global dispersion of metals in the environment.
Man, animals and plants are exposed to a
variety of metals through environment, food,
water and soil. Metals being non-
biodegradable persist in the environment for a
long period and causes serious eco-
toxicological problems. Additionally, many
metallic compounds like zinc, copper,
calcium, trivalent chromium, and iron being
essential to life have formed complex bio-
geochemical cycles. Essential elements are
involved in a variety of critical functions
including the control of gene transcription,
nerve conductance and oxygen transport and
as active centers in enzymes. Therefore, the
critical molecular events within the cell such
as gene expression, cell proliferation and cell
death are affected by trace elements. Some
toxic metals may mimic the essential metals
and thereby gain access to important
molecular targets. It is flawless that toxic
metals can together activate and inactivate the
cellular procedures regimented by the
indispensable metals. Even crucial metals can
be toxic too. An uncommon of the
environmental metals, i.e., arsenic, chromium
is carcinogenic.
Apoptosis is considered as an ongoing normal
event in the control of cell populations.
However, apoptosis can also be induced by a
variety of xenobiotics including many of the
toxic metals resulting in the loss of affected
cell populations. Apoptosis essentially occurs
when cellular damage, including damage to
genetic material, has exceeded the capacity for
repair (Figure 1).
Environmental metals can damage apoptosis
and that suppression of the apoptotic response
could expedite aberrant cell accumulation,
which may be a life-threatening step in the
pathogenesis of malignancy or autoimmunity.
One of the primary genes shown to regulate
apoptosis was Bcl-2. Consequently, a number
of Bcl-2 related proteins were also recognized.
Although, the overwhelming evidence that
Bcl-2 proteins are evolutionarily preserved
regulators of apoptosis, their specific
biochemical function remains scandalous.
There have been a multitude of reports
showing that enforced over expression of Bcl-
2 or of Bcl- XL acts to delay the onset of
Cadmium and Apoptosis Shagirtha and Miltonprabu
RRJoT (2016) 1-10 © STM Journals 2016. All Rights Reserved Page 2
apoptosis induced by toxicants. The vast
majority of these reports concentrates on
apoptosis induced by DNA-damaging agents
in cancer cell lines and concludes that Bcl-2 or
Bcl-XL renders the cells drug resistant.
Programmed cell death is a highly regulated
but double-edged sword, it is crucial to
developmental processes in multicellular
organisms but loss of regulatory control is
implicated in a growing number of diseases,
including inflammation, malignancy,
autoimmunity and neuro degeneration.
Fig. 1: Apoptosis.
Apoptosis-related genes have been identified
in most of the tissues and successful
characterization of such genes presents
potential targets for specific pharmacological
intervention in a wide range of diseases. Many
pathological conditions can be attributed
directly or indirectly to defects in the
regulation of apoptosis that result in either a
cell accumulation, in which cell eradication or
cell turn-over is impaired, or cell loss, in
which the cell-suicide program is
inappropriately triggered. Identification of the
genes and gene products liable for apoptosis,
together with evolving information about the
mechanisms of action and configurations of
apoptotic regulatory and effector proteins, has
positioned a foundation for the discovery of
drugs, few of which are now undergoing
evaluation in human clinical trials. It is in
present increasingly accepted that part of the
efficacy of conventional chemotherapeutic
drugs is due to their knack to induce apoptosis
with the goal of providing death signals and
revoking survival signals. There is a wide
range of novel approaches to the induction of
apoptosis by down regulating survival
signaling along with many alternative
strategies aimed at targeting particular
molecular abnormalities of neoplastic cells as
a means of inducing apoptosis (Figure 2).
An outline of the apoptotic pathway with
arrows (-) representing activation and circles
(K) representing inhibition. Remarkably,
apoptosis reconciled by death receptors (Fas L,
TNF) and by the damage of survival factors
Research & Reviews: A Journal of Toxicology
Volume 6, Issue 1
ISSN: 2231-3834(online), ISSN: 2349-1264(print)
RRJoT (2016) 1-10 © STM Journals 2016. All Rights Reserved Page 3
use miscellaneous signaling pathways, though
a convergence between these two pathways is
observed at the mitochondria. A sum of
toxicants can change the rate of apoptosis. For
example, the carcinogenic transition metals,
chromium, cadmium and nickel are proficient
of causing an increase in apoptosis along with
DNA base modifications, strand breaks and
rearrangements. The tenacity of this review is
to recapitulate current understanding of the
apoptotic pathways commenced by toxic as
well as indispensable metals. Characterization
of apoptosis-related genes might be obliging in
pharmacological interpolation in metal-
induced pathologies.
Fig. 2: Apoptotic Pathways Representing Inhibition.
Cadmium
Cadmium (Cd) may exert both acute and
chronic influences on human health. Acute
poisoning has occasionally occurred in the
past mainly because of inhalation of fumes
emanating at the time of dissolving or
breakage of substances containing Cd or when
soldering with silver-cadmium solder. Chronic
poisoning occurs habitually under conditions
when there is an inadequate protection in
industries handling Cd-containing material and
in circumstances where environmental
contamination causes prominent levels of Cd
in food. In the superior airway, chronic
inflammation of the nose, pharynx, and larynx,
as well as olfactory turbulences are
experiential. In the inferior airway, chronic
obstructive lung disease of fluctuating severity
is established. The renal injury induced by Cd
exposure is an extremely distinctive disorder.
It was verified from a survey of 12,559
inhabitants of a Cd-polluted section and 6435
inhabitants of Cd-polluted region in Japan.
The furthermost severe form of chronic Cd
poisoning caused by prolonged oral Cd
ingestion is Itai-Itai disease. The scientific
picture of Itai-Itai disease shows renal injury
demonstrated by tubular and glomerular
dysfunction and bone injury comprising of a
amalgamation of osteomalacia and
osteoporosis.
Cadmium and Apoptosis Shagirtha and Miltonprabu
RRJoT (2016) 1-10 © STM Journals 2016. All Rights Reserved Page 4
Cadmium Toxicity
Cadmium is one of the most notorious heavy
metals. Cadmium inhibits plasma membrane
calcium channels and Ca2+ ATP ase groups
and hence can inhibit enzymes; however, cells
treated with cadmium showed proliferation of
peroxisomes that contain the enzyme catalase.
In addition, cadmium inhibits gluconeogenesis
and oxidative phosphorylation. Cadmium is a
direct enzyme poison. It exerts toxic effects on
the lung, kidney, liver and immune system
(Figure 3).
Fig. 3: Effects of Cadmium Leading to Apoptosis.
Apoptosis
Cadmium is known to induce apoptosis in
human T cells, mouse thymocytes, human
mononuclear cells, kidney cell lines,
myocardial cells, smooth muscle cells, mouse
liver cells and C6 glioma cells [1–5]. The
susceptibility to cadmium-induced apoptosis is
dependent on basal or induced level of MT,
which binds cadmium to prevent toxic
damage. In addition, it has been testified that
cadmium modifies the protein kinase,
phosphatase activities and transcription factors
and MAPK. Mitochondrial, caspases and ROS
passageways all looks like to show a role in
cadmium-induced apoptosis. These
characteristics of apoptosis as appraised by
Orrenius [6] are demonstrated by Figure 4.
Bak, Bcl-2 homologous antagonist/killer; Bax,
Bcl-2-associated X protein; Bid,
BH3interacting domain death agonist; Cyt.c,
cytochrome-c; Apaf-1, apoptosis activating
factor-1; CD95L, CD95 ligand; FADD, Fas-
associated death domain; AIF, apoptosis
inducing factor; EndoG, endonuclease G;
HtrA2/Omi, high- temperature requirement
protein A2 [6].
It was publicized that cadmium could directly
lead to the dysfunction of isolated
mitochondria from mouse liver, containing the
inhibition of respiration, the foundation of
permeability transitionpore (PTP), the loss of
transmembrane potential and the discharge of
cytochrome C [7]. Still, these mitochondrial
Research & Reviews: A Journal of Toxicology
Volume 6, Issue 1
ISSN: 2231-3834(online), ISSN: 2349-1264(print)
RRJoT (2016) 1-10 © STM Journals 2016. All Rights Reserved Page 5
changes were absolutely suppressed by Bcl-xL
and ruthenium red. Cadmium affected the PTP
opening possibly through its binding to thiol
groups of adenine nucleotide translocator
(ANT). They concluded that mitochondrial
pathway may involve cadmium-induced
apoptosis. Cadmium induced apoptosis was
found to be accompanied by caspase-3
activation [8]. Both these events could be
reversed by N-acetyl-Asp-aldehyde (Ac-
DEVD-CHO), a selective caspase-3 inhibitor,
indicating that the caspase-3 pathway is
involved in cadmium-induced apoptosis in
cortical neurons. Cadmium-induced toxicity
was intermediated via, ectopic manifestation
of apoptosis during development [9].
Fig. 4: Receptor- and Mitochondria-mediated Apoptotic Pathways.
In cadmium-treated embryos, considerably
greater numbers of apoptotic cells were
observed by confocal microscopy. Tunel assay
and fluid cytometry were also engaged to
examine the dynamics of apoptosis. Cd-
induced apoptosis was found to be mediated
by a mechanism involving intracellular GSH
reactive oxidation [10]. In another study, it
was clearly shown that mitochondria play a
key role in the cascade of events leading to
apoptosis in the hepatocytes of rainbow trout
after exposure to cadmium. There exist a
relationship between oxidative stress and cell
death [11]. The special effects of cadmium on
isolated oyster hemocytes, the utmost immune
system in mollusks were scrutinized by
Sokolova et al. [12]. They validated that in
this organism also Cd2+ induces apoptosis
Cadmium and Apoptosis Shagirtha and Miltonprabu
RRJoT (2016) 1-10 © STM Journals 2016. All Rights Reserved Page 6
through a mitochondrial/caspase-independent
pathway, signifying that a novel perhaps
ancient apoptotic pathway is vigorous in these
cells. Studies using cDNA microarray and
quantitative realtime PCR assay to determine
the gene expression profiles in the testes of
CD-1mice after a single subcutaneous
injection of 5 mmol/kg CdCl2 showed
increased expression of the c-myc and Egry
genes suggesting acute stress responses [13].
Decreased expression of proapoptotic genes,
particularly caspase-3 and DNA repair genes
possibly contributes to Cd-induced
carcinogenesis. Expression of Bcl-2 and p53 in
relation to apoptosis was studied in the porcine
renal proximal tubule epithelial cells (LLC-
PK1) [14]. They suggested that the apoptosis
of LLC-PK1cells induced by cadmium might
be associated with the inhibition of the
expression of Bcl-2 and p53.c-junN-terminal
kinase (JNK) and c-jun signaling cascade play
a crucial role in Cd-induced neuronal cell
apoptosis and provides a molecular linkage
between oxidative stress and neuronal
apoptosis [15]. Cd2+ toxicity in epithelial lung
cells was also investigated [15].
They revealed that MAPK p38 appeared to be
tangled in the Cd-induced apoptosis in Clara
cells and type2 cells. The commotion of PKC
was put forward to have a non-judgmental role
in the apoptotic process, situated upstream of
p38 phosphorylation. An evaluation of
cadmium toxicity in plants and mammalian
cells was prepared [16]. He suggested that
features, viz. ability to remove the oxidized
proteins, slightly different regulation of cell
cycle genes, and specific pattern of apoptosis
make plants more resistant to Cd2+-induced
uncontrolled cell proliferation. Recently it was
demonstrated that toxic metal TM-induced
apoptosis in cultured murine podocytes
through the extrinsic Fas-FADD caspase
8pathway, rather than the mitochondrial
apoptotic pathway [17]. They further
concluded that combined exposure to toxic
metals induces less apoptosis than the
individual exposure to arsenic,
cadmium and mercury.
Metallothionein (MT)-3expression determined
the choice between apoptotic or necrotic cell
death in Cd-induced human proximal tubule
cells. It was shown that cells which express
MT-3 undergo necrosis when exposed to Cd2+
whereas cells that have no basal expression of
MT-3 undergo apoptotic cell death. They
confirmed that the unique N-terminal sequence
of MT-3 is required to elicit an effect on the
mechanism of the Cd2+-induced death of the
proximal tubule cell [18]. An expeditious and
tranisient ROS generation by cadmium
triggered apoptosis via caspase-dependent
alleyway and successive mitochondrial
pathway [19]. N-acetylcysteine (NAC)
obstructs Cd-induced apoptosis through
blocking ROS generation as well as the
catalase upregulation. Piperine (a plant
alkaloid) modulated Cd-induced alterations in
murine thymocytes. The study demonstrated
the antioxidative, antiapoptotic and restorative
ability against cell proliferative mitogenic
response suggesting its therapeutic usefulness
in immuno compromised conditions [20].
Another study reported that antioxidants and
caspase3inhibitors, viz: NAC and silymarin
blocked cadmium-induced apoptosis [21].
Cd-induced apoptosis in the testis of a dog fish
was studied (Squalus acanthias) using
fluorescence technique [22]. He showed that
Cd2+ targets only the spermatogenic stages
where it specifically activates a cell death
program in susceptible spermatogonial clones
and negatively affects blood-testis barrier
function. Question of apoptotic resistance was
also addressed by a few workers. Cadmium
exposed rat liver epithelial cells were found to
be resistant to apoptosis induced by high
concentration of cadmium [23]. It was
predicted to be linked with a specific
dominance of the JNK pathway and
accompanying with MT over expression which
in turn may affect the signal transduction
pathway. The attainment of apoptotic
resistance might play an essential role in
cadmium carcinogenesis via tumor initiation
and malignant progression. The execution of
apoptosis/necrosis in cadmium-treated human
promonocytic cells under different forms of
oxidative stress was also studied [24]. They
suggested the existence of two different
oxidation-mediated necrotic pathways in
cadmium-treated cells, one of them resulting
from ATP- dependent apoptosis and the other
involving the concurrence of multiple
regulatory factors.
Research & Reviews: A Journal of Toxicology
Volume 6, Issue 1
ISSN: 2231-3834(online), ISSN: 2349-1264(print)
RRJoT (2016) 1-10 © STM Journals 2016. All Rights Reserved Page 7
Cd-induced apoptosis suppresses of NF-kB
activity which may be mediated by oxidative
stress [25]. The absence of apoptotic death
was correlated with a specific defect in
activation of Bax. JNK dependent regulation
of Bax is essential to mediate the apoptotic
release of cytochrome c regardless of Bid and
Bim activation [26]. Recent investigation on
Cd-induced apoptosis introduces to a few new
concepts, viz. apoptotic resistance, MT-
3expression and suppression to NF-
kB. Relationship between metallothionein and
apoptosis in the liver and lung of rat has also
been studied by Gurel et al. [27]. They
reported that cadmium can suppress apoptosis
in vivo. The possible role of MT expression on
the suppression of apoptosis and the
importance of free- Cd ion concentration on
switching antiapoptotic effects to proapoptotic
effects was discussed.
Similarly a relationship between glutathione
and apoptosis was also recorded [28]. They
demonstrated greater apoptosis in T cells in
CD4 (+) than CD8 (+) cells related to higher
depletion of intracellular glutathione.
Cadmium at 5–20 mmol/kg could induce
hepato cellular DNA damage, expression of
proto-oncogenes c-myc, c-fos, c-jun as well as
apoptosis in rats. Cadmium caused apoptosis
in LLC-PK1cell, which was partially
suppressed by pretreatment with selenium
[29]. Molecular mechanisms of toxicity
Cadmium-induced changes in the expression
of MT, p53 and proto-oncogenes such as c-jun
may be important for the development of
prostatic and testicular tumors in rats. One of
the most extensively studied properties of MTs
relates to the hypothesis that they protect the
cell against cadmium toxicity [30]. Studies in
which the primary iso forms of MT (MT-1and
MT-II) are knocked out in mice have shown
that these mice were more susceptible to
cadmium toxicity than control mice [31–33].
In addition, when MT-1was over-expressed in
transgenic mice, cadmium was less lethal and
produced less nephrotoxicity at levels of
exposure to cadmium that injured control mice
expressing normal amounts of MT-1 [34].
Other studies have cautioned that MTs are not
the sole factor in determining Cd toxicity,
because only a subset of the adverse effects of
Cd can be prevented by MT. Testicular
necrosis in mice exposed to Cd could not be
blocked by the over- expression of MT-1but
this may be because Cd was injected, and there
was not enough time to induce MT as there
would be if exposure occurred by ingestion
[35].
In addition, progesterone-induced synthesis of
MT actually increased cadmium cytotoxicity
in rat liver cell [36]. MT can also increase the
residence times of toxic metals in the body,
which may lead to chronic effects when
protective mechanisms are overwhelmed [37].
Cd-induced cellular response with respect to
apoptosis is summarized below: Release of
cytochromeC from mitochondria [7]. Caspase-
3activation [8], Intracellular GSH oxidation
[10], Inhibition of the expression of Bcl2 and
p53 [14], Involvement of Fas-FADD caspase8
pathway in murine podocytes [18], N-terminal
sequence of MT-3 is required to induce
apoptosis in proximal renal tubular cells [19].
CONCLUSIONS
There appears to be no unifying mechanism by
which metals act to alter the apoptotic process.
However, understanding the mechanisms of
apoptosis caused by carcinogenic and non-
carcinogenic metals may open new avenues to
manipulate cells during metal toxicity. In a
kindred fashion, enhanced apoptosis may
ravage concrete critical cell populations or
may sanction damaged cells to elude
congruous eradication. Suppression of
apoptosis may facilitate aberrant cell
accumulation which may be critical step in the
pathogenesis of malignancy or autoimmunity.
A cell must contain a controlling mechanism
governing the decisive bifurcation between the
proliferative and antiproliferative states
including growth arrest, differentiation,
cellular aging and apoptosis. Understanding
proliferation controls is therefore fundamental
for understanding controls in other cellular
processes. Experimental evidence proved that
caspases and mitochondria both play important
roles in the initiation and execution of
apoptosis. In the intrinsic pathway death
signals act directly or indirectly on the
mitochondria, resulting in the release of
cytochrome c and formation of the
Cadmium and Apoptosis Shagirtha and Miltonprabu
RRJoT (2016) 1-10 © STM Journals 2016. All Rights Reserved Page 8
apoptosome complex. Importance of
mitochondrial antioxidant defense system in
the regulation of apoptosis has long been
recognized.
Over recent years, many new cell cycle and
apoptosis-related molecules have been
discovered, often with indistinct roles.
Survivin is a bifunctional molecule that has a
role both as an inhibitor in apoptosis and an
orchestrator of cell division; the resulting
cross-verbalize between the processes
promotes a balance between proliferation and
death with limits on the magnification and
survival of cells suffering oncogenic
mutations. It has become increasingly clear
that intracellular proteolysis via the
ubiquitin/proteasome pathway has a
fundamental role in cell cycle regulation,
protein degradation in mitosis and apoptosis,
as well as in other fundamental physiological
processes including antigen processing, signal
transduction, transcription and the flux of
substrates through metabolic pathways. The
calcium-dependent thiol proteases, calpains,
are widely expressed with ubiquitous and
tissue concrete isoforms. Calpains have been
implicated in rudimental cellular processes
including cell proliferation, apoptosis,
differentiation, cytoskeletal rearrangements
and cell migration.
In integration to the massive array of
molecules now kenned to be involved in cell
division and cell death, another ever-
incrementing list of molecules involved in
cognate processes has been developed.
Hyaluronan, a high molecular weight
glycosaminoglycan, is an extra cellular matrix
component of tissues that facilitates cell
locomotion which plays a major role in wound
rejuvenating, cell proliferation, mitotic cell
rounding, de-adhesion and migration.
Furthermore, recent studies have shown that
hyaluronan is involved in the intracellular
regulation of the cell cycle and gene
transcription. Disorders of apoptosis and cell
accumulation may play critical roles in some
of the most severe and debilitating metal-
induced afflictions including neuro toxicity,
hepatotoxicity, renal toxicity, autoimmunity
and carcinogenesis. Developing the
mechanisms of aberrant apoptosis resulting
from metal exposure may allow the
development of novel preventive strategies in
Cadmium poisoning.
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Cite this Article
Shagirtha and Miltonprabu. Cadmium
and Apoptosis: A Molecular Approach.
Research and Reviews: A Journal of
Toxicology. 2016; 6(1):