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All content in this area was uploaded by Raj narayan Roy on Aug 14, 2021
Content may be subject to copyright.
Content uploaded by Raj narayan Roy
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All content in this area was uploaded by Raj narayan Roy on Aug 14, 2021
Content may be subject to copyright.
Poll Res. 40 (1) : 227-235 (2021)
Copyright © EM International
ISSN 0257–8050
NICKEL ESSENTIALITY, TOXICITY AND THE MECHANISM OF
TOXICITY IN ANIMAL
RAJ NARAYAN ROY*
Department of Botany, Dr. B.N. Dutta Smriti Mahavidyalaya,
Hatgobindapur, Purba-Bardman 713 407, West Bengal, India
(Received 9 July, 2020; accepted 28 August, 2020)
ABSTRACT
Nickel is one of the prevalent heavy metal pollutants. The sources of this pollutant are both natural
as well as anthropogenic. The ongoing increase of the modern technology is gradually increasing
the demand for nickel-containing product. The use of nickel in modern technology is gradually
increasing that result in hastened consumption of nickel-containing product. Nickel compounds
contaminate our environment during its manufacturing as well as its usage. Their rapid
accumulation in different locations of the earth is hazardous. Human society is ultimate facing
various adverse effects of nickel toxicity along with all other creatures on the earth. Though, as a
micronutrient nickel is important for normal functioning of the animal system but at the elevated
concentrations it causes various adverse effects. Through this review article efforts are being made
for an analysis of the existing situation related to essentiality, effect and mechanism of nickel
toxicity on animals. The investigation at the current scenario is extremely crucial for the realization
of the extent of the crisis linked to nickel as an environmental toxicant to accelerate awareness and
search for remedy.
KEY WORDS : Micronutrient, Environmental hazard, Heavy metal, Allergen, Animal
INTRODUCTION
Nickel, the silver-white heavy metal can exist in
different oxidation states. However, the
predominant oxidation state available at nature is
Ni(II), the +2 valence state. The other valences (-1,
+1, +3, and +4) are available in less frequently.
Nickel is a silver-white metal available in different
oxidation states (from -1 to +4), though the primarily
available form in the biological system is [Ni(II)], +2
oxidation state (Coogan et al., 1989). Natural sources
of nickel include wind-blown grime from the
process of weathering of rocks and soils, volcanic
emanations, fires on forest and vegetation. However,
nickel also release to environment due to the
burning of coal and fuel oil, waste and sewage, and
miscellaneous sources (Grandjean, 1984). The hassle
less availability of a variety of nickel alloys rapidly
accelerating it use in modern technologies. At
present nickel is widely used in stainless steel, alloys
of nickel and nickel cast iron together with objects
including electrical equipment, artillery, machinery,
tools, ornaments and domestic utensils. The nickel is
also used for electroplating, electroforming, mordant
of dye, batteries of nickel-cadmium alkaline,
catalysts electronic equipment and other varied
sources together with cement manufacture as well
(Duda-Chodak and Blaszczyk, 2008). The
advancement of the technology assures improved
living standard but invites different defies on
environmental security. Limitless industrialization
along with urbanization without sufficient emission
control as well as pollution diminution has thrust
our lives to the threat. The inflowing of nickel in the
human environment from natural and
anthropogenic sources globally amounts around 150
000 and 180 000 metric tons respectively annually
(Kasprzak et al., 2003). Underdeveloped economic
condition of the developing countries encourage
them to bypass the guidelines related to
environmental protection (Ikhuoria and Okieimen
2000; Sahu and Arora, 2008). To get the way of
228 RAJ NARAYAN ROY
remedy of nickel toxicity at this crucial moment it is
necessary to have aneloquent idea on the nature and
magnetite of toxicity on the living kingdom.
Thisreview article will be helpful to create adequate
awareness leading to find the way for its proper
remedy that we have to come across.
Essentiality of Nickel in animal
Nickel is an essential trace element for the animal
including human (Wintz et al., 2002; Cempel and
Nikel, 2006). The insufficiency of nickel is linked
with the histological and biochemical changes as
well as reduced iron reabsorption and interaction
with haeme iron leads to anemia. It can perturb the
absorption of calcium into skeleton resulting in
parakeratosis-like damage (Anke et al., 1984). King et
al. (1985) are of opinion that nickel might provide as
a cofactor for the activation of calcineurin, a
calmodulin-dependent phosphoprotein
phosphatase. The essential role of nickel ions
consists of the action or the formation of cGMP, a
signaling agent responsible for the regulation of
various physiological processes. Among these, blood
pressure control, sodium metabolism,
cardiovascular health and sperm physiology are
noteworthy.
Nickel is consistently exists in RNA and is linked
to several biological components such as proteins
(insulin, keratin), amino acids and serum albumin
(Yokoi et al., 2002). Insufficiency of nickel may lead
to disturbing in the transmission of the genetic code.
Insufficiency of nickel also hinders the growth,
decrease reproductive rates and change the
metabolism of glucose and lipid that are linked to
anemia, hemoglobin reduction, alternations of metal
ion contents, and reduced efficiency of several
enzymes (Samal and Mishra, 2011). In the course of
nerve transmission, muscle excitation and
contraction, nickel can alternate for calcium
(Howard, 2003).
It exists in the human being as well as rabbit
serum in three forms i.e., nickel bound to
ultrafilterable ligands, albumin-bound nickel and
macroglobulin bound nickel. The chief transport
protein for this metal is albumin in the human being;
rat as well as in bovine sera. Nickeloplasmin, a
metalloprotein has been separated from the rabbit
sera ( -2 macroglobulin) and the human being (-
glycoprotein) (USPHS 1993). Ultrafilterable nickel
binding ligands take an important part in
extracellular transportation and exclusion of nickel
in urine. L- histidine of human serum found as
nickel-binding ingredient with greater affinity than
that of albumin. Albumin nickel L- histidine, a
ternary complex intervene the replace and relocate
nickel between L - histidine and albumin (Sigel and
Sigel, 1988).
Toxic effect of nickel on animal
Genotoxicity: Nickel can induce a number of
genetic abnormalities such as DNA strand break
(Liu et al., 2013), DNA methylation (Sun et al., 2013),
DNA-protein cross-links (Tretyakova et al., 2015),
nucleotide excision repair system (Hartwig et al.,
2002), gene mutations (Morales et al., 2016),
epigenetic gene silencing (Sun et al., 2013),
exchanges of sister chromatid, micronuclei, nucleic
acid concentration alteration as well as cell
transformation (Coogan et al., 1989; Costa, 1991; Das
and Dasgupta, 2000) in higher organisms. Inhibition
of the ligation step of excision repair within the
ovary cells of Chinese hamster by nickel has also
reported (Lee-Chen et al., 1993).
It appears that protein is the primary objective for
nickel insult (Lynn et al., 1997). Nickel may
accountable for the increased concentration of
endogenous cellular hydrogen peroxide and its
short-lived ROS (Lynn et al., 1997; Das et al., 2001).
Through the damage of nuclear protein, nickel may
cause an epigenetic alteration by reducing the
activity of enzymes essential for DNA replication,
transcription and recombination repair (Sun et al.
2013).
Developmental toxicity: Chashschin et al. (1994)
have reported structural malformations within the
newborns of women worker of a hydrometallurgy
refining plant of nickel. In experimental rats
inhalation of high levels of nickel during gestation
may result in decreased fetal body weight (Weischer
et al., 1980). Parental administration of this heavy
metal may also affect the developmental process in
animals (Chernoff and Kavlock, 1982). Nickel is not
able to cross the placental barrier (Clarkson et al.,
1985; Odland et al., 1999). In vitro study advocates
that nickel salts have the potential to damage the
placental tissue (Chen and Lin, 1998).
Neurotoxicity: Neurological effects such as
giddiness, weariness etc has observed in persons
unintentionally open to the nickel and boric acid in
drinking water (Sunderman et al., 1988). Prolong
nickel toxicity may lead to neurological signs such as
lethargy, ataxia, prostration, within experimental
rats (American Biogenics Corporation, 1988).
Recently, it has established that nickel-induced
NICKEL ESSENTIALITY, TOXICITY AND THE MECHANISM OF TOXICITY IN ANIMAL 229
toxicity produces oxidative stress in mitochondria
that make it dysfunctional that ultimately damages
nerve (Xu et al., 2010; Song et al., 2017).
Hematotoxicity: Through the studies of Weischer et
al. (1980) and the National Toxicology Programme,
(NTP 1996)a, b, c a number of hematological
alterations have observed as an effect of nickel
toxicity. Nickel above the permissible level may
cause a transient rise in blood reticulocytes
(Sunderman et al., 1988). Works of literature are
available about an increase in leukocyte as well as
platelet counts and levels (American Biogenics
Corporation, 1988), decreased the erythrocyte count,
hematocrit value, and hemoglobin concentration
(Das et al., 2007). Such a decrease could create nickel-
induced anemia (nonregenerative anemia) initiating
from injury of haematopoietic stem cells. In rats,
nickel toxicity may consequences in decreases of all
kinds of blood cells by hampering the activity of the
bone marrow (Das et al., 2007). Nickel deficiency has
not been made known to be a concern in humans,
despite this; it may cause biochemical changes, such
as reduced Fe resorption that directs to anemia
(Divya and Karthikeyan, 2017).
Immunotoxicity: Nickel can be responsible for
noticeable immune and allergic reactions (Dearman
and Kimber, 1992; Kimber and Dearma, 1994;
Guimaraens et al., 1994; Das et al., 2008). Exposure of
animals, including human to nickel extensively
boost in the level of immunoglobulin G (IgG), IgA
and IgM. However, there a noteworthy drop off in
IgE levels has been noticed (Das et al., 2008). A
sizeable rise in other serum proteins, including á1-
antitrypsin, 2-macroglobulin, ceruloplasmin, may
be connected with the cell-mediated immunity that
has also been recognized (Bencko et al., 1983; Bencko
et al., 1986). Exposure to nickel significantly
increases vulnerability to infection of Streptococcus
(Adkins et al., 1979), reduce in antibody titers against
viral antigen (Figoni and Treagon, 1975; Graham et
al., 1978). Li and Zhong (2014) reported that NiCl2
increases the secretion of a pro-inflammatory
cytokine, interleukin-1_ (IL-1_), in bone marrow-
derived macrophages and bone marrow dendritic
cells.
Reproductive toxicity: Nickel beyond its
permissible level may amplify the rate of
spontaneous abortions in human (Chashschin et al.
1994). The toxic effect of this heavy metal has linked
with the testicular degeneration (NTP 1996 a,b,c).
Several testicular malformations, such as
proliferation of interstitial cell, decline in the count
of spermatozoa and effect on a number of testicular
enzymes viz., steroid 3ß hydroxysteroid
dehydrogenase were also seen in male due to nickel
toxicity (EPA 1985). Das et al. (2001) have pointed
decreased count and motility of sperm and
modification of steroidogenesis in nickel-treated
rats. Nickel exposure at toxic concentration elevates
the level of testicular lipid peroxidation and reduces
the functionality of the antioxidant enzyme in rats
(Gupta et al. 2007). Kakela et al. (1999) observed that
NiCl2 encourage shrinkage of the seminiferous
tubules and reduced the count of spermatogonia
within the tubules.
Carcinogenicity: Ni+2 compounds are powerful
carcinogens and capable to persuade malignant
transformation of the cells of rodent as well as
human beings (Oller et al., 1997; Kasprzak et al.,
2003; Goodman et al., 2009; Xu et al., 2010). It was
found experimentally that exposure to elevated
concentrations of nickel may result in adenomas,
adenocarcinomas, carcinomas of squamous cell and
fibrosarcoma (Ottolenghi et al., 1974; Horie et al.,
1985).
However, a considerable rise in the occurrence of
alveolar/ bronchiolar adenoma or carcinoma has
been reported in male and female rats exposed due
to nickel toxicity (National Toxicology Programme
1996c). The available works of literatures advocate
that mechanistically, nickel carcinogenicity is utmost
likely to be the consequence of genetic factors and/
or direct or indirect epigenetic factors.
Conformational change is the important direct
epigenetic factor, whereas in case of an indirect
epigenetic factor, the generation of oxygen radicals
is important. In addition, certain nickel compounds
uphold cell proliferation, through the conversion of
repairable DNA lesions into non-repairable ones
(Das et al., 2008).
On liver: Liver is badly affected due to nickel
toxicity. It may be associated with increased serum
bilirubin, induced a degenerative effect on hepatic
tissue (Das et al., 2006), massive alteration at normal
hepatic architecture along with the manifestation of
vacuolated cytoplasm (fatty liver), eccentric nuclei
and Kupffer cell hypertrophy. The decreased in
functionality of hepatic and renal transaminase due
to nickel toxicity have also reported in rats. The
activity has found more adverse in a protein-
restricted diet schedule (Das and Buchner, 2007). A
decrease in liver ascorbic acid, as well as cholesterol
levels, may also result due to nickel toxicity (Das and
Dasgupta, 1998). A significant rise in hepatic lipid
230 RAJ NARAYAN ROY
peroxides, a decline in antioxidant enzymes like
superoxide dismutase (SOD), catalase (CAT) as well
as glutathione peroxidase (GSH-Px) activities and in
the concentration of hepatic glutathione has been
reported due to the toxicity of nickel in rats (Das et
al., 2001)
Toxicity on lungs: Nickel toxicity may responsibility
for histological alteration of the lungs. Induced
alveolar wall damage, fibrotic changes along with
oedema in the alveolar space leading to lung cancer
have reported due to nickel toxicity (Lu et al., 2005).
Substantial raise in the rate of recurrence deaths
owing to respiratory disease has also documented in
welders (Cornell and Landis, 1984). Inhalation
exposure to various compounds of nickel such as
nickel sulphate, nickel subsulphide, or nickel oxide
may lead to the most well-known effect in the lungs
as chronic active inflammation (ATSDR, 2003).
Water-soluble nickel sulphate may have an intense
consequence on the tissue of the lung as well as its
enzyme system responsible for antioxidant activities
(Gupta et al., 2006). A noteworthy rise in the level of
lipid peroxide in lung tissue and, lung SOD, CAT
and the significant decrease in GSH-Px activities has
also been reported (Gupta et al., 2006).
Toxicity on kidneys: Nickel, after its entry within
the body, it is carried by blood and retains by
different tissues or excretes mainly through urine.
As a result, the kidney becomes vital vulnerable
target organ of nickel toxicity as well as
carcinogenicity (Kadi and Dahdouh, 2016).
Cytotoxicity of the nickel is well recognized that
may consist of diverse cell lines together with
kidney cells (Kadi and Dahdouh, 2016). Nickel
toxicity may generate reactive oxygen species which
may lead to lipid peroxidation and oxidation of
DNA as well as proteins resulting in cell apoptosis
and nephrotoxicity (Chakraborty and Bai, 1999;
Wang et al., 2012). Transient increase of albumin in
urine has also been documented (Sunderman et al.
1988).
Increased concentrations of nickel in urine among
the workers of nickel refinery are considerably
associated with urinary 2-microglobulin levels
(Sunderman, 1981). The incidence of damage of
renal tubular at the junction of corticomedullary has
also observed (Sunderman et al., 1988). A significant
drop off in the volume of urine as well as levels of
glucose in urine and an increase in relative kidney
weight has also documented (Obone et al., 1999).
Toxicity on skin: In 1925, dermatitis among the
workers of the nickel-plating industry has been
reported (Counts et al., 2002). This is an allergic
reaction commence due to make get in touch with
nickel (Namikoshi et al., 1990; Counts et al., 2002).
Presently most of the reported common allergens
reactions are owing to the contact of nickel. As
incidences are gradually increasing, it is turning as
foremost health and socio-economic a problem of
several countries (Wojciechowska et al., 2015). It is
reported that adults and children are hypersensitive
to nickel 13% and 8% respectively (Czarnobilska et al.,
2007).
Fig. 1. Molecular mechanism of nickel toxicity in animal
NICKEL ESSENTIALITY, TOXICITY AND THE MECHANISM OF TOXICITY IN ANIMAL 231
Nickel is accountable for creation sensitivity
reactions which may be of both short- and long-
lasting. Females are more susceptible to nickel
toxicity in comparison to that of the male due to
wearing of nickel-containing ornaments (McDonagh
et al., 1992). Once developed, it continued for the rest
of life (Sharma, 2007). Allergy to nickel may have
cutaneous as well as systemic manifestations. A
systemic nickel allergy syndrome is a harsh type of
allergy. It can be clinically distinguished by
cutaneous symptom with a chronic course and
systemic symptoms. The cutaneous manifestations
include contact dermatitis, pompholyx, hand
dermatitis dyshidrosis as well as urticaria. Most of
the important systemic symptoms are itching,
asthenia, headache and gastrointestinal disorders
associated with histopathological variations of
gastrointestinal mucosa, borderline with celiac
disease (Tammaro et al., 2011).
Allergic nickel dermatitis is also a major
occupational hazard as work tools and ingredients
may discharge nickel in profuse quantity leading to
professional exposure in industries (Thyssen et al.,
2011). In 2008, nickel has received the disgraceful
indication of the “Allergen of the Year” (Gillette,
2008).
Mechanism of toxicity of nickel on animal
Though the molecular means of toxicity on the
animal has must investigate but it is not much clear
about their detail mechanism. We have tried to give
a diagrammatic representation of conceivable idea
about the molecular means of nickel toxicity from
the literature available (Fig. 1). It has documented
that nickel may as active as a blocker of calcium
channel and liable for alteration in calcium
metabolism (Zamponi et al., 1996). At elevated
concentrations, nickel may impair absorption or
utilization of iron when its concentration is low.
Nickel beyond permissible level is very efficient at
turning off the expression of thrombospondin I (TSP
I) a protein liable for the regulator of tumor
expansion (Salnikow et al., 1997). TSP at high
concentration suppresses the progression of blood
vessels into the tumor body.
In nickel-transformed cells ATF-1, the
transcription factor is hyper-activated and acts on
thrombospondin I like a negative regulator.
Therefore, repression of TSP I expression in tumors
accelerate angiogenesis and stimulates tumor
growth. The concentration of another transcription
factor, hypoxia-inducible factor 1 (HIF-1) is also
increased due to nickel toxicity (Salnikow et al.,
2002a,b). HIF-1 facilitates angiogenesis which is
crucial for tumor development. Like hypoxia, Ni(II)
induces HIF-1 and therefore activates genes liable
for the up-regulation of metabolism of glucose as
well as glycolysis even in the occurrence of oxygen,
the vascular endothelial growth factor, and the
tumor marker Cap43 (Zhou et al., 1998; Salnikow et
al., 2000a,b).
Nickel toxicity is also accountable for
inflammatory response through regulation of
expression of transcription factors responsible for
inflammatory progression. The transcription factor
NF-êB is activated due to nickel toxicity and
transforms cellular as well as tissue responses. The
consequence of which is nickel-induced allergic
effects along with contact hypersensitivity of skin
(Viemann et al., 2007). NF-êB plays a significant role
in apoptosis, inflammatory 693 responses, and
expression of adhesion molecules. Nickel toxicityup-
regulate intercellular adhesion molecule-1of human
endothelial cells, vascular cell adhesion molecule-1,
and endothelial leukocyte adhesion molecule-1
(Goebeler et al., 1993).
The means through which nickel harm the
animals, particularly in human, had the long been
highlighted on oxidative reactions relating to lipids,
proteins, and DNA. It is also known that nickel can
binds to a diversity of biomolecules and alter their
properties (Das et al., 2008; Kasprzak and Salnikow,
2007). At present, it is documented that nickel is able
to have intense effects on DNA or histone
methylation ensuing in epigenetic effects as well as
on DNA repair (Chen and Costa, 2009; Chen et al.,
2010; Sekirnik et al. 2010).
Nickel-induced transformation may be linked
with the mutation of the gene p53 (Denkhaus and
Salnikow, 2002). It is a tumor suppressor gene and
transcription factor concerned with the regulation of
cell proliferation and apoptosis. Human cancer is
generally associated with the mutations in the p53
gene. Maehle et al. (1992) have documented that
nickel toxicity may cause mutation of the p53 gene
in epithelial kidney cells of the human being.
Another gene FHIT (Fragile Histidine Triad)
responsible for suppressor of the tumor is located in
a fragile chromosomal site sensitive to deletions. In
tumors as well as in pre-malignant lesions its
expression is generally reduced or lost. During
complex communication with diadenosine
triphosphate, the gene product Fhit protein
(phosphohydrolase) may induce apoptosis. In vitro
232 RAJ NARAYAN ROY
study has revealed that nickel creates a well-built
inhibition on the enzymatic activity of Fhit protein
and also represses Fhit expression in nickel-
transformed BALB/c-3T3 cells.
Nickel toxicity increases the degree of DNA
methylation and histone deacetylation resulting in
the inactivation of the expression of the gene
(Martinez-Zamudio and Ha, 2011). This inactivation
of the gene accountable for tumor suppressor by
hypermethylation could assist in nickel-induced cell
transformation. Beside it, in vitro silencing of the
gene through the hypermethylation, a suppressive
outcome of nickel on acetylation of histone H4 has
also been documented both in the cell of yeast and
human being (Broday et al., 2000). Works of
literature on the damage of DNA and chromatin in
nickel-exposed cells and tissues are abundant.
However, the mutagenic potentiality of this nickel,
in general, is considered to be low (Fletcher et al.,
1994).
CONCLUSION
In spite of being a heavy metal, nickel is necessary
for animals to lead a successful life. In the animal
deficiency of nickel may be associatedwith the
alternation of the histological and biochemical
characters and reduction of iron resorption as well
as interaction with heme iron leads to anemia. This
heavy metal may also be responsible for the
progression of parakeratosis-like damage through
perturbing the calcium absorption into the skeleton.
Nickel has drawn much consideration as an
intoxicating pollutant for the emergent
anthropogenic stress on the environment. On the
other hand, lung fibrosis, contact dermatitis,
cardiovascular and kidney diseases, as well as lung
and nasal cancers, is the most important and
prevalence in animals. In 2008, nickel has marked
through the disgraceful identity of the “Allergen of
the Year”. Still, it to be explored at the molecular
level. Surplus nickel brings on oxidative stress.
Although, the mechanism linked to generation of
nickel toxicity at the protein and molecular level
may be explored in detail. The reclamation of soils
polluted by heavy metals can be achieved with
dierent techniques and technologies including cost
effective biological technique-the phytoremediation.
However, the solutions to this problem are
important and need further research. This review
will be helpful to conceive an in-depth idea in
related to the nature and magnitude of nickel
toxicity in animal which is very essential to fight
against this environmental issue.
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