Impact of heavy metals on the environment and human health: Novel therapeutic insights to counter the toxicity

Abstract

Heavy metals are well-known environmental pollutants owing to their toxicity, longevity in the atmosphere, and ability to accumulate in the human body via bioaccumulation. The pollution of terrestrial and aquatic ecosystems with toxic heavy metals is a major environmental concern that has consequences for public health. Most heavy metals occur naturally, but a few are derived from anthropogenic sources. Heavy metals are characterized by their high atomic mass and toxicity to living organisms. Most heavy metals cause environmental and atmospheric pollution, and may be lethal to humans. Heavy metals can become strongly toxic by mixing with different environmental elements, such as water, soil, and air, and humans and other living organisms can be exposed to them through the food chain. Plenty of experimental studies were performed to appraise the promising treatment options from natural products. Additionally, nanotechnology based treatment options are being constantly developed. As an emerging field, nanotechnology is making substantial advances in the analysis and removal of heavy metals from complicated matrices. Removal of heavy metal has been accomplished by the use of a variety of nanomaterials, including graphene and its derivatives, magnetic nanoparticles, metal oxide nanoparticles, and carbon nanotubes, to name a few. Using nanotechnology for heavy metal analysis and removal from food and water resources provides many benefits over traditional methods. These advantages include a broad linear range, low detection and quantification limits, a high sensitivity, and high selectivity. Therefore this review aimed to explore the environmental consequences of the heavy metals, toxicity to the human health, as well as novel therapeutics development from the natural resources. Additionally, nanotechnological and nanomedicinal applications to treat heavy metal toxicity are also highlighted in this review.

Full text

Impact of heavy metals on the environment and human health: Novel
therapeutic insights to counter the toxicity
Saikat Mitra
a
, Arka Jyoti Chakraborty
a
, Abu Montakim Tareq
b
, Talha Bin Emran
c,
⇑
, Firzan Nainu
d
,
Ameer Khusro
e
, Abubakr M. Idris
f,g
, Mayeen Uddin Khandaker
h
, Hamid Osman
i
, Fahad A. Alhumaydhi
j
,
Jesus Simal-Gandara
k,
⇑
a
Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh
b
Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh
c
Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
d
Faculty of Pharmacy, Hasanuddin University, Tamalanrea, Makassar 90245, Indonesia
e
Research Department of Plant Biology and Biotechnology, Loyola College, Chennai, Tamil Nadu, India
f
Department of Chemistry, College of Science, King Khalid University, Abha, Saudi Arabia
g
Research Center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia
h
Centre for Applied Physics and Radiation Technologies, School of Engineering and Technology, Sunway University, Bandar Sunway, Selangor 47500, Malaysia
i
Department of Radiological Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
j
Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi Arabia
k
Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Faculty of Food Science and Technology, University of Vigo–Ourense Campus, E32004 Ourense,
Spain
article info
Article history:
Received 13 November 2021
Revised 14 January 2022
Accepted 20 January 2022
Available online 29 January 2022
Keywords:
Heavy metals
Environmental health
Toxicity
Nanotechnological approaches
Nanomedicine
abstract
Heavy metals are well-known environmental pollutants owing to their toxicity, longevity in the atmo-
sphere, and ability to accumulate in the human body via bioaccumulation. The pollution of terrestrial
and aquatic ecosystems with toxic heavy metals is a major environmental concern that has consequences
for public health. Most heavy metals occur naturally, but a few are derived from anthropogenic sources.
Heavy metals are characterized by their high atomic mass and toxicity to living organisms. Most heavy
metals cause environmental and atmospheric pollution, and may be lethal to humans. Heavy metals can
become strongly toxic by mixing with different environmental elements, such as water, soil, and air, and
humans and other living organisms can be exposed to them through the food chain. Plenty of experimen-
tal studies were performed to appraise the promising treatment options from natural products.
Additionally, nanotechnology based treatment options are being constantly developed. As an emerging
field, nanotechnology is making substantial advances in the analysis and removal of heavy metals from
complicated matrices. Removal of heavy metal has been accomplished by the use of a variety of nanoma-
terials, including graphene and its derivatives, magnetic nanoparticles, metal oxide nanoparticles, and
carbon nanotubes, to name a few. Using nanotechnology for heavy metal analysis and removal from food
and water resources provides many benefits over traditional methods. These advantages include a broad
linear range, low detection and quantification limits, a high sensitivity, and high selectivity. Therefore
this review aimed to explore the environmental consequences of the heavy metals, toxicity to the human
health, as well as novel therapeutics development from the natural resources. Additionally, nanotechno-
logical and nanomedicinal applications to treat heavy metal toxicity are also highlighted in this review.
Ó2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access
article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
1. Introduction
Periodic table consists of heavy metals to a notable portion with
high density and atomic weight. Among them, the majorities are
found in the biosphere, such as in water, soils, and rocks, and are
also released into the surroundings from anthropogenic resources,
mostly commercial and industrial. The toxic principles of heavy
metals have been known for decades. However, recent experimen-
tal investigations show that some, including nickel, copper, and
https://doi.org/10.1016/j.jksus.2022.101865
1018-3647/Ó2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
⇑
Corresponding authors.
E-mail addresses: talhabmb@bgctub.ac.bd (T.B. Emran), jsimal@uvigo.es (J.
Simal-Gandara).
Peer review under responsibility of King Saud University.
Production and hosting by Elsevier
Journal of King Saud University – Science 34 (2022) 101865
Contents lists available at ScienceDirect
Journal of King Saud University – Science
journal homepage: www.sciencedirect.com

zinc, are vital for humans and are widespread in nature (Azeh
Engwa et al., 2019). Manganese is found all over the world and
makes about 0.1 percent of the earth’s crust. However, heavy met-
als have such a number of undesirable repercussions on the envi-
ronment; for example, the conversion of mercury into
methylmercury in the presence of water creates sediments with
high toxicity (Rice et al., 2014). Chromium is used extensively in
industry and can be carcinogenic (Coetzee et al., 2020). However,
some heavy metals are involved in the control of certain physio-
logic bodily functions. Naturally found vital heavy metals pene-
trate into the body via food, air, and water, where they regulate
numerous biological activities (Chasapis et al., 2012; Roohani
et al., 2013).
Most of the toxic heavy metals including lead, thallium, cad-
mium, and antimony, are common in industrial operations and
are substantial polluters of the environment. Thallium has a more
severe effect than other heavy metals, but is less abundant in nat-
ure (Karbowska, 2016); it is a cause of alopecia in humans. The
benefits of heavy metals are generally outweighed by their haz-
ards; for example, carcinogenicity is promoted by high exposure
to antimony and chromium (Sun et al., 2015; Sundar and
Chakravarty, 2010), lead poisoning causes intellectual abnormali-
ties in children (Hou et al., 2013). Mercury toxicity causes Mina-
mata disease, while cadmium poisoning causes itai-itai disease.
Heavy metals can also cause toxicity in certain organs of the
human body, such as nephrotoxicity, neurotoxicity, hepatotoxicity,
skin toxicity, and cardiovascular toxicity, among other things. To
avoid toxic effects, it is necessary for people to move away from
industrial areas where heavy metal emission is considerable.
Many treatment procedures have been developed to counteract
the toxicity of heavy metals. Natural products are being efficiently
used to treat the adverse consequences (Singh et al., 2011;
Tchounwou et al., 2012). Medicinal herbs and natural products
for the treatment of various diseases have been around for almost
the entire survival of mankind. One of the most significant advan-
tages of traditional or plant-based medicine seems to be its per-
ceived effectiveness, as well as its low frequency of severe
adverse responses and its relatively cheap cost. Experimentally
induced heavy metal toxicity in laboratory animals was signifi-
cantly reduced using a variety of medicinal herbs and natural prod-
ucts (Bhattacharya, 2018).
Nanotechnological approaches are also seeking attention due to
promising benefits on eradication of the adversative consequences
of heavy metals. Nanotechnology is the use of interdisciplinary
methods of creating nanoscale materials or devices that include
concepts from physics, chemistry, engineering, and biology. With
the rise of nanotechnology, nanomaterials for heavy metal detec-
tion and removal have been painstakingly developed and manufac-
tured, providing countless benefits (He et al., 2019b).
This review aims to provide a clear explanation of the toxic con-
sequences of heavy metals and the impact on the environment.
Therefore, nanotechnological, nanomedicinal, and natural products
based therapeutic strategies to counter the toxicity are also high-
lighted in this review.
2. Heavy metals in the environment
Heavy metals naturally occur in the environment and are vital
for survival, but they may become hazardous when they accumu-
late in organisms. A few of the most frequent heavy metals that
contaminate the environment include mercury, cadmium, arsenic,
chromium, nickel, copper, and lead (Hazrat et al., 2019).
Cadmium is released into the atmosphere as a result of natural
or manmade activities and animals and humans can be exposed to
it differently. Cadmium pollution of the aquatic environment
occurs through absorption, industrial waste, and surface runoff
into sediments soil and sediments. People can be poisoned by
cadmium via ingesting food, breathing air, or drinking water rich
in the metal. Cadmium does not have any attributes that are
helpful for plant growth and metabolic processes (Hayat et al.,
2018).
Mercury is an extremely hazardous heavy metal that may be
found in biosphere. Due to human activities, it has also become a
widespread contaminant and is increasing in the atmosphere. Mer-
cury converts to the highly toxic methylmercury when in contact
with aquatic sediments (Gworek et al., 2020). Methylmercury
enters the human body through the food chain via fish, seafood,
and wildlife, which become contaminated after ingestion of toxic
microorganisms. It penetrates the circulation after being absorbed
into the human body and causes a variety of neurological problems
(Rice et al., 2014).
Lead is a non-biodegradable metal that is available in nature
and found in relatively low amounts. Atmospheric lead levels are
increasing continuously because of the human activities including
manufacturing, mining, and fossil fuel burning. Lead is toxic to the
human body when exposed to amounts greater than the optimum.
Children are at higher risk of lead poisoning; when they come into
contact with dust laden with environmental lead, the severity of
poisoning increases (Loh et al., 2016).
Manganese, the most plentiful of the toxic heavy metals, is
found in various oxidation states in nature. During combustion of
methylcyclopentadienyl manganese tricarbonyl (MMT), an addi-
tive in gasoline, manganese oxides are emitted into the air.
Although manganese is required for a variety of physiological
activities, excessive consumption results in substantial toxicity
(Loranger and Zayed, 1995; O’Neal and Zheng, 2015).
Chromium is a cancerous and toxic element. In the environ-
ment, it exists in two stable oxidation states: chromium (III) and
chromium (IV) (VI). Chromium (III) is a less hazardous form of
chromium (VI). They can interconvert to each other during indus-
trial operations. However, conversion of chromium (VI) to chro-
mium (III) is less harmful to the environment because the latter
is lower in toxicity. Chromium is used in many industries that pose
a threat to regional climates. In comparison to natural chromium
emissions from the environment, ferrochrome industry emissions
are at the highest level (Fig. 1)(Coetzee et al., 2020; Kimbrough
et al., 1999).
Cobalt is found in abundance across the environment, such as
vegetation, soils, rocks, and water and is utilized to make alloys.
Although its rate of discharge is low, it is highly dangerous to
humans. Cobalt affects the human body in both beneficial and
harmful aspects. The little amounts of cobalt usually have no neg-
ative consequences, but massive discharges into the environment
can cause fatalities (Domingo, 1989).
Nickel is a naturally abundant element and has extensive indus-
trial uses. It is emitted from both natural and anthropogenic
sources into the atmosphere (Li et al., 2016a). It has many adverse
effects on humans, and causes allergies, nasal and lung cancer, and
kidney and cardiovascular diseases owing to the inhalation of con-
taminated air (Genchi et al., 2020; Lu et al., 2005).
Copper is recognized as a vital micronutrient for living organ-
isms. It has a role in normal physiological functions of plants, such
as formation of chlorophyll, photosynthesis, and carbohydrate and
protein metabolism. Copper deficiency alters important metabolic
processes, and elevated exposure causes toxicity (Schwartz et al.,
2003).
Zinc is a fundamental and omnipresent metal. It is associated
with plenty of enzymatic reactions via acting as a cofactor. Zinc
toxicity depends on the manner and quantity of exposure. Smelt-
ing and mining are major the sources of zinc. A large amount of
zinc emitted into the environment originates from the activities
S. Mitra, Arka Jyoti Chakraborty, Abu Montakim Tareq et al. Journal of King Saud University – Science 34 (2022) 101865
2

of mineral processing and affects ecosystems as well as living
organisms (Zhang et al., 2012).
Antimony is a poisonous element that may be found in nano-
gram amounts in the air. Natural occurrences, including volcanic
activity and weathering, as well as anthropogenic activities, cause
emissions into the atmosphere (He et al., 2019a). Antimony toxic-
ity develops in those working in industrial areas from inhalation
(Fig. 1). Antimony poisoning causes physiological shortcomings,
including pancreatitis, cardiotoxicity, and respiratory problems
(pleural adhesions, chronic emphysema, chronic bronchitis, respi-
ratory irritation, and inactive tuberculosis). It is also carcinogenic
and affects reproduction (Sundar and Chakravarty, 2010).
Thallium is found in the environment in many forms and is haz-
ardous to biological organisms. Thallium’s toxicity is greater tha-
n any other heavy metal. Monovalent thallium ions arise in
natural water and are emitted into the air via aqueous route
(Fig. 1)(Peter and Viraraghavan, 2005). In addition, industrial
emissions are a major contributor to the increase in thallium levels
in the atmosphere. Exposure to thallium is extremely harmful to
humans (Kazantzis, 2000).
3. Bioaccumulation of heavy metals in living system
Any essential or non-essential trace elements that are present
in excess of the safe levels may result in physiological or morpho-
logical abnormalities or genetic mutations, such as slowing or
stopping growth or causing mutations (Khan et al., 2010; Li et al.,
2010; Luo et al., 2011). Food crops are one of the most essential
components of our nutrition, and they may include a variety of
both necessary and hazardous metals (Waqas et al., 2015; Yang
et al., 2011), based on the properties of the growth medium used.
Human exposure to heavy metals comes mostly through edi-
ble vegetables, which account for around 90% of the overall intake,
while the remaining 10% comes from skin contact and breathing of
polluted dust (Khan et al., 2014; Kim et al., 2009; Martorell et al.,
2011). Because of the growing demand for food in recent decades,
food safety has become a major public health concern in terms of
human health. This scenario serves to motivate researchers and
scientists to do study on the health risks linked with the ingestion
of heavy metals, pesticides, and toxin-contaminated food products
(Jaishankar et al., 2014).
Our food chain is constantly being replenished with essential
and non-essential materials as a result of the excessive use of agro-
chemicals, municipal wastewater, industrial effluents, and raw
sewage for irrigation (Tongesayi et al., 2013). In accordance with
the Agency for Toxic Substances and Disease Registry’s toxicity
classification system, heavy metals and metalloids such as arsenic,
lead, and cadmium present in the environment are classed as 1, 2,
and 7 on a scale from 1 to 7 (ATSDR, 2007).
Mineral resources and elements such as copper, chromium,
iron, manganese, and zinc, among others, are essential for both ani-
mals and humans because they are involved in a variety of meta-
bolic functions, enzyme activities, receptor sites, hormonal
function, and protein transport at specific concentrations
(Antoine et al., 2012). Another group of elements, such as arsenic,
cadmium, lead, and mercury, are non-essential and play no useful
role in plants, animals, or people. They also serve no nutritional
purpose since they are exceedingly poisonous (Khan et al., 2015).
To set quality standards and identify the hazards to human health
and food safety, it is required to describe the sources and amounts
of heavy metals in soil (Sun et al., 2013). Environmental pollution
caused by heavy metals is persistent, covert, and long-term (Ali
et al., 2019). Because metals are nonbiodegradable and have a
lengthy half-life, biological species are unable to decompose them,
and they remain in their body parts and surroundings, posing
health risks (Nabulo et al., 2011). Bioaccumulation of heavy metals
Fig. 1. Diagrammatic explanation about heavy metals in the environment.
S. Mitra, Arka Jyoti Chakraborty, Abu Montakim Tareq et al. Journal of King Saud University – Science 34 (2022) 101865
3

in vegetables poses a health hazard due to their potential to trans-
fer from polluted land and water into the food chain (Khan et al.,
2015; Stasinos and Zabetakis, 2013).
Soil properties are crucial in food production, and heavy metal
pollution of this critical resource, as well as their subsequent
absorption and bioaccumulation in food crops, poses substantial
environmental and health concerns, especially in poor countries.
Heavy metal concentrations are influenced by soil type, plant
genotype, and their interactions (Ding et al., 2013). In comparison
to organic manure, mineral fertilizers contain increased concentra-
tions of heavy metals; as a consequence, the use of mineral fertil-
izers leads in increased levels of heavy metal pollution in soil (Hu
et al., 2013).
The health risks associated with toxic metals are dependent on
the concentrations of these metals in certain media and the length
of exposure. Even at low quantities of hazardous metals, long-term
and chronic exposure may cause health problems (Mahalakshmi,
2012). Heavy metal toxicity is one of the principal abiotic stressors
on plants, and it is based on heavy metal physiochemical features
(Saxena and Shekhawat, 2013).
4. Toxicity of heavy metals
4.1. Neurotoxicity
As an essential element, manganese is involved in several phys-
iological functions of the body. Its acute exposure exerts potential
neuroprotective action by reducing apoptotic cellular death but
exposure to a large quantity may induce harmful conditions alike
neurological complications, such as alzheimer and parkinson dis-
ease which leads to apoptotic cell death and alteration of home-
ostasis (Goldhaber, 2003). Homeostasis of the cellular Mn relies
on sufficient intake, storage, as well as excretion via different cell
receptors and ion channels. The receptors associated with metal
uptaking are down-regulated by homeostatic pathways in terms
of excessive Mn exposure, whereas those engaging in its discharge
from this cell become up-regulated. However, ongoing Mn accu-
mulation leads to the increased formation of ROS, which con-
tributes to mitochondrial dysfunction. Mitochondrial
dysfunctions result in the discharge of cytochrome c, stimulating
the apoptosis precursor caspase-9, by which caspase-3 cleaves.
The cleaved caspase-3 fragment binds to a pro-apoptotic protein,
PKCd(protein kinase C delta). The proteolytic cleavage of PKCd
induced by Caspase-3 contributes to DNA fragmentation, as well
as apoptosis (Fig. 2)(Harischandra et al., 2019).
The central nervous system suffers from cognitive impairment
when arsenic is consumed. It’s also linked to a number of neurolog-
ical illnesses, including neurodevelopmental changes, and leads to
excessive of neurodegenerative diseases. Arsenic poisoning also
causes changes in synaptic transmission and neurotransmitter bal-
ance (Garza-Lombó et al., 2019). Additionally, the neurotoxic
effects of arsenic are attributed to induce multiple apoptotic mech-
anisms. Firstly, arsenic and its methylated metabolites facilitates
caspase- induced apoptosis in neural cells via the MAPK signaling
pathways that include the ERK2, JNK, or p38; follow the intrinsic
mitochondrial-apoptotic mechanisms. Besides, arsenic initiates
intracellular calcium upturn that arbitrates apoptosis. On the con-
trary, cellular apoptosis can be mediated by activation of autop-
hagy via the stimulation of the AMPK as well as inhibition of the
mammalian target of rapamycin (mTOR). Autophagy is referred
to a homeostatic manner where double-membraned autophago-
some erupt cellular constituents to be eventually degraded when
fused with lysosomes (Garza-Lombó et al., 2019).
Neurodegenerative defects, including amyotrophic lateral scle-
rosis, Parkinson’s disease, Alzheimer’s disease, and multiple sclero-
sis, result from neurotoxicity induced by cadmium (Branca et al.,
2018). Numerous preclinical evidences have revealed that cad-
mium severely affects the functionalities of PNS (Miura et al.,
2013) and CNS (Marchetti, 2014), with many clinical manifesta-
tions, such as peripheral neuropathy, olfactory dysfunctions, neu-
rological disturbances, learning disabilities, and mental
retardation, along with the impairment of motor function and
behavioral changes in both adults and children. Additionally, many
types of cellular activity, such as cell differentiation, proliferation,
and cell death, are affected. The neurotoxicity of cadmium arise
from neural cell death via apoptosis; providing plenty of
apoptosis-induction factors, including impairment of neurogene-
sis, inhibition of neuron gene expression, offering epigenetic effect,
endocrine disruption, etc. (Wang and Du, 2013).
Pathological investigations of poisoned animals and humans
demonstrate that thallium toxicity causes damage to the brain
and peripheral nerve. It produces edema and vascular engorge-
ment in the cerebral hemispheres, capillary alterations in the brain,
cerebellar edema with pyknotic Purkinje cells, and isolated regions
of necrosis (Davis et al., 1981).
In addition to manganese, arsenic, and cadmium, a lot of heavy
metals have been established for their neurotoxic consequences.
As well, copper and zinc, like iron, act as impediments to neurode-
velopment when an excessive amount enters the brain (Prohaska,
2000). Excess copper retention causes Wilson’s disease, a heredi-
tary condition which causes neurobehavioral abnormalities similar
to schizophrenia. Zinc deficiency has an adverse influence on neu-
rodevelopment, but the consequence of vast quantities is not clear
(Cai et al., 2005). An experimental study by Ken-ichiro Tanaka and
Masahiro Kawahara showed that copper augments zinc-induced
neurotoxicity (Tanaka and Kawahara, 2017).
4.2. Nephrotoxicity
Nephrotoxicity induced by cadmium leads to intense clinical
symptoms such as glucosuria, Fanconi-like syndrome, phospha-
turia, and aminoaciduria (Hazen-Martin et al., 1993; Reyes et al.,
2013). The proximal tubular epithelium is affected by direct expo-
sure to the kidneys, resulting in a significant level of cadmium in
urine, aminoaciduria, 32-microglobulinuria, and glucosuria, as well
as impaired renal tubular phosphate reabsorption (Goyer, 1989).
Renal tubular acidosis, renal failure, and hypercalciuria can all
result from excessive exposure (Friberg et al., 2019; Jacquillet
et al., 2007).
Lead has deleterious effects in all organs, but it has the greatest
influence on the kidneys. Acute lead nephropathy causes proximal
tubular dysfunction, resulting in Fanconi-like syndrome. Chronic
lead nephropathy can be characterized by hyperplasia, interstitial
fibrosis, atrophy of the tubules, renal failure, and glomerulonephri-
tis (Fig. 2).
Acute exposure of the kidneys to mercury causes acute tubular
necrosis, and has many clinical symptoms, such as acute dyspnea,
altered mental status, abdominal pain, profuse salivation, tremors,
vomiting, chills, and hypotension. In contrast, chronic exposure to
mercury causes injury to the epithelium and necrosis in the pars
recta of the proximal tubule. Tubular failure, higher urine excretion
of albumin and retinol-binding protein, and a nephritic state with a
characteristic of membranous nephropathy are all symptoms of
mercury-induced chronic kidney injury (Lentini et al., 2017).
Thallium sulfate excretion via the kidneys is delayed and can
take up to two months after consumption. Toxic injury to the kid-
neys is indicated by albuminuria and hematuria. However, thal-
lium poisoning does not cause gross diminishment of renal
function (Yumoto et al., 2017).
S. Mitra, Arka Jyoti Chakraborty, Abu Montakim Tareq et al. Journal of King Saud University – Science 34 (2022) 101865
4

4.3. Carcinogenicity
Arsenic causes epigenetic alterations, damage to DNA, changes
in the p53 protein’s expression, histone modifications, DNA methy-
lation, and reduced p21 expression (Fig. 2)(Martinez et al., 2011;
Park et al., 2015). Arsenic poisoning raises the risk of cancer by
attaching to DNA-binding proteins and slowing down the DNA-
repair process (Garcia-Esquinas et al., 2013).
Lead is a carcinogenic substance that causes damage to the DNA
repair mechanism, cellular tumor regulating genes, and chromoso-
mal structure and sequence by releasing ROS (Fig. 2). It disrupts
transcription by shifting zinc from certain regulatory proteins.
(Silbergeld et al., 2000).
Mercury’s peroxidative activity generates a significant quantity
of reactive oxygen species (ROS), which can aid protumorigenic
signaling and cancerous cells growth. ROS can contribute to car-
cinogenesis by damaging cellular proteins, lipids, and DNA, result-
ing in cell damage (Reczek and Chandel, 2017; Zefferino et al.,
2017).
Nickel works as a carcinogen via controlling a variety of car-
cinogenic mechanisms, including gene regulation, transcription
factor management, and free radical generation. It controls the
expression of particular long non-coding RNAs, mRNAs, and micro-
RNAs. It participates in the methylation of the promoter and the
downregulation of gene 3 (MEG3) to increase the modulation of
hypoxia-inducible factor-1, both of which contribute to carcino-
genesis (Zambelli et al., 2016; Zhou et al., 2017).
4.4. Hepatotoxicity
The toxicity of lead on liver cells is well established. Exposure to
it increases oxidative stress resulting in liver damage. Organic sol-
vents, combined with lead, also cause injury to the liver because of
having the same characteristics as lead (Farmand et al., 2005;
Fig. 2. Mechanism of heavy metal toxicity in human.
S. Mitra, Arka Jyoti Chakraborty, Abu Montakim Tareq et al. Journal of King Saud University – Science 34 (2022) 101865
5

Malaguarnera et al., 2012). Chronic lead exposure is potentially
toxic to liver cells, resulting in glycogen depletion and cellular infil-
tration, which can result in chronic cirrhosis (Fig. 2)(Hegazy and
Fouad, 2014).
Cadmium has two human target tissues: the renal cortex and
the liver (Bernard, 2004). During acute exposure, it accumulates
in the liver and is linked to a variety of hepatic dysfunctions. Cad-
mium changes the cellular redox balance, resulting in oxidative
stress and hepatocellular damage (Zalups, 2000). Hepatotoxicity
induced by cadmium, both acute and chronic, causes liver failure
and therefore can increase the risk of cancer (Hyder et al., 2013).
Copper is well known to accumulate in the liver due to Wilson’s
disease. Increased levels of copper may cause oxidative stress;
therefore, hepatic copper deposition is not only pathognomonic,
but also pathogenic. Elevated hepatic copper levels are also
observed in cholestatic liver diseases. However, they result from
diminished biliary excretion of copper and are not a cause of hep-
atic infection (Deering et al., 1977; Gross et al., 1985; Yu et al.,
2019).
Numerous studies have shown that Cr(VI) can harm the liver,
and histopathological changes such as steatosis of hepatocytes,
parenchymatous degeneration and necrosis were already identi-
fied. Elevated ROS levels, lipid peroxidation, suppression of DNA,
RNA, and protein synthesis, DNA damage, decrease of antioxidant
enzyme activity, mitochondrial dysfunction, such as impaired
mitochondrial bioenergetics, cell growth arrest, and apoptosis are
all associated with Cr(VI) hepatotoxicity (Hasanein and
Emamjomeh, 2019).
4.5. Immunological toxicity
Acute and chronic lead exposure leads to several toxic effects on
the immune system and causes many immune responses, such as
increased allergies, infectious diseases, and autoimmunity, as well
as cancer (Dietert et al., 2004; Hsiao et al., 2011). A high risk of
lung, stomach, and bladder cancer in several demographic groups
has been linked to lead exposure (Rousseau et al., 2007;
Steenland and Boffetta, 2000). Exposure to lead triggers the pro-
duction of B and T-cells as well as MHC activity (Kasten-Jolly
et al., 2010). It can influence cellular and humoral responses by
modifying the role of T-cell and increasing susceptibility to devel-
opment of autoimmunity and hypersensitivity (Fig. 2)(Mishra,
2009).
Occupational and environmental exposure to cadmium may
induce immunosuppressive effects based on varying exposure con-
ditions. Humoral immune responses are amplified at low exposure,
whereas the effects at higher exposures are not yet established.
However, phagocytosis, natural killer cell activity, and host resis-
tance in experimental infections are notably reduced in most cases.
Laboratory studies on exposure of mice and rodents to heavy
metals resulted in many immunological defects, including
immunosuppression and immunostimulation. Injection of mercury
chloride into mercury-insensitive strains of laboratory animals’
reduced cellular function in the immune system, i.e., the animals
showed immunosuppression. When mercury was applied to
mercury-sensitive rodent strains, cellular activity in the immune
system was enhanced, i.e., the animals showed immunostimula-
tion. Both immunosuppression and immunostimulation lead to
infections, allergies, and autoimmune diseases. However, mercury
does not appear to have an impact on the human immune system,
although Swedish authors have concluded that amalgam, a mer-
cury alloy, affects the immune system.
Chromium is known to have many adverse effects on the
human immune system. The influence of chromium on the
immune system has been explored in numerous experimental
studies. According to Faleiro et al. who used CoCrMo disc samples,
lymphocyte proliferation is obstructed. High doses of hexavalent
chromium reduce the phagocytic action of alveolar macrophages
and the humoral immune response (Glaser et al., 1985). In addi-
tion, chromium induces two types of hypersensitivity reactions:
type I (anaphylactic type); and type IV (delayed type). Develop-
ment of allergic contact dermatitis due to chromium exposure
has also been found in many studies (Bruynzeel et al., 1988;
Leroyer et al., 1998).
4.6. Cardiovascular toxicity
Lead exposure, either acute or chronic, produces a variety of
abnormalities in the human body. Chronic exposure to lead may
cause arteriosclerosis and hypertension, thrombosis, atherosclero-
sis, and cardiac disease by increasing OS, reducing NO availability,
increasing vasoconstrictor prostaglandins, altering the renin–an-
giotensin system, lowering vasodilator prostaglandins, disrupting
vascular smooth muscle Ca
2+
signaling, increasing inflammation
and endothelium-dependent vasorelaxation, and adjusting the vas-
cular response to vasoactive agonists. Exposure for a long time also
increases arterial pressure (Hertz-Picciotto and Croft, 1993; Vaziri,
2008, 2002).
Cadmium is a toxicant and carcinogenic metal. In addition to its
carcinogenic properties, cadmium induces kidney disease, bone
disease, and cardiovascular disease (Toxicological Profile for
Cadmium, 2002). Low to moderate cadmium exposure results in
hypertension (Tellez-Plaza et al., 2008), diabetes (Schwartz et al.,
2003), carotid atherosclerosis (Messner et al., 2009), peripheral
arterial disease (Navas-Acien et al., 2004), chronic kidney disease
(Hellström et al., 2001), myocardial infarction (Everett and
Frithsen, 2008), stroke, and heart failure (Peters et al., 2010). In
prospective studies, cadmium was linked to an increased risk of
cardiovascular death in the general population of the United States
(Tellez-Plaza et al., 2013, Tellez-Plaza et al., 2012).
Mercury has been shown to cause neurotoxicity, nephrotoxic-
ity, and hepatotoxicity in humans. Cardiovascular toxicity has also
been discovered in recent research. Levels of mercury in hair have
been linked to oxidized LDL levels in atherosclerotic lesions, acute
coronary failure and atherosclerosis (Yoshizawa et al., 2002).
Paraoxonase, an extracellular antioxidative enzyme linked to HDL
dysfunction, is likewise inactivated by mercury (Gonzalvo et al.,
1997; Salonen et al., 1999); this is directly linked to the progres-
sion of atherosclerosis and the increased risk of a coronary heart
disease, cardiovascular disease, acute myocardial infarction, coro-
nary heart disease, and carotid artery stenosis (Kulka, 2016).
Cobalt exposure causes reversible systolic cardiac depression,
which may be distinguished from other cardiomyopathy disorders.
Cardiomyopathy caused by cobalt can be slow and fatal. However,
the cardiac function of survivors usually recovers (Packer, 2016).
Increased T cell proliferation
4.7. Skin toxicity
Chronic arsenic exposure promotes a lot of possible skin dis-
eases, including hyperkeratosis, hyperpigmentation, and several
types of skin cancer. Hyperpigmentation is the most prevalent skin
change caused by prolonged arsenic exposure. Arsenic exposure
can potentially cause Bowen’s disease, a type of early skin cancer.
Arsenic hyperkeratosis is usually widespread, affecting the soles
and palms, but it can also affect the legs, toes, fingers, arms, and
dorsum of the hands. Some hyperkeratotic and Bowen’s disease
lesions have the potential to develop into invasive malignancies
(Huang et al., 2019).
The skin, the body’s outermost organ, serves as a barrier against
different contaminants. Contact with chromium causes a variety of
acute and chronic severe dermatological consequences, including
S. Mitra, Arka Jyoti Chakraborty, Abu Montakim Tareq et al. Journal of King Saud University – Science 34 (2022) 101865
6

contact dermatitis, systemic contact dermatitis, and skin cancer.
Contact dermatitis is a common skin disorder characterized by
delayed hypersensitivity as a result of recurrent dermal contact
with allergens (haptens) (Fig. 2). Systemic contact dermatitis is a
kind of dermatitis induced by systemic exposure to an allergen,
which causes the skin to become sensitive through direct dermal
contact at first (Matthews et al., 2019; Menné et al., 1994; Uter
et al., 2018; Winnicki and Shear, 2011; Yoshihisa and Shimizu,
2012).
Many skin infections are caused by mercury and mercury-
containing compounds, including such acrodynia (pink disease), a
common dermatological ailment in which the skin becomes pink
when exposed to heavy metals, particularly mercury (Horowitz
et al., 2002). People tattooed with the red pigments cadmium sul-
fide and mercury sulfide may have inflammation restricted to
specific areas typically within six months after getting tattooed
(Boyd et al., 2000). Moderate swelling, scaling, vesiculation, and
irritation are symptoms of acute contact dermatitis caused by
mercury-containing substances. According to several studies, mer-
cury poisoning is the most prevalent cause of dermatological prob-
lems (Boyd et al., 2000).
4.8. Reproductive and developmental toxicity
Arsenic is a known reproductive toxin in humans, and it causes
abnormalities in experimental animals, particularly neural tube
anomalies (Wang et al., 2006). Inorganic arsenic impairs male
reproduction by reducing the weights of the testes, the accessory
sex organs, and the number of sperm in the epididymis. Aside from
affecting sperm production, inorganic arsenic exposure also causes
variations in testosterone and gonadotropin levels, as well as dis-
turbances in the steroidogenesis process (Kim and Kim, 2015). In
females, arsenic consumption is associated with an increased inci-
dence of endometrial cancer (Salnikow and Zhitkovich, 2008).
Endometrial angiogenesis, which is critical for embryo develop-
ment, is then impaired by arsenic exposure during pregnancy.
Symptoms of endometriosis, subfertility, prematurity, sterility,
and spontaneous abortions are all caused by these conditions
(Milton et al., 2017).
Several studies conducted by the World Health Organization
(WHO) have found that more than 10% of women are at risk of
infertility because of their exposure to heavy metals such as lead,
cadmium, mercury, and other pollutants, which are the most com-
mon environmental contaminants that can cause reproductive dis-
orders (Apostoli and Catalani, 2011). According to a study
conducted by the WHO, the condition of infertility is mostly more
prevalent in women than in men. Ovulation disturbances are a fre-
quent cause of subfertility in women (Naz and Batool, 2017;
Upadhyay et al., 2020). Ovulation disturbances are characterized
by irregular or absent menstrual cycles, and they may be corrected
with the use of reproductive hormones. The risk of infertility in
women elevated as a result of increasing levels of toxin exposure,
which resulted in hormonal disruption, delayed ovulation, and
chromosomal abnormality in oocytes. Female infertility is caused
mostly by hormonal imbalance, which is exacerbated by endocrine
disruption caused by heavy metal poisoning, which is the most
common cause of female infertility currently (Fig. 2)(Rattan
et al., 2017).
4.9. Genotoxicity
Several investigations have shown significant interindividual
variability in receptiveness to arsenic poisoning, with genetic fac-
tors as the fundamental source of this variability being identified.
The genotoxicity of arsenic results in deoxyribonucleic acid alter-
ation, which includes chromosomal abnormalities, mutation,
micronuclei production, deletion, and sister chromatid exchange
(Roy et al., 2018). Numerous investigations have been conducted
to determine the mechanism of arsenic’s genotoxic impact, which
includes the induction of oxidative stress and the disruption of
DNA repair (Pierce et al., 2012). Arsenic has been shown to have
no direct effect on DNA and is regarded as a weak mutagen
because, despite its low mutagenicity, it impacts the mutagenicity
of other carcinogens. In human cells, for example, an increased
mutagenicity of arsenic has been found when exposed to UV light
(Yin et al., 2019).
The genotoxic effects of human exposure to chemical com-
pounds cause changes in the genetic material primarily via two
processes: teratogenesis and carcinogenesis. Teratogenesis is a
process in which a chemical compound causes changes in the
genetic material. The first of these may manifest itself in the off-
spring in the form of congenital abnormalities, whilst the second
manifests itself in the development of malignancies in those who
have been exposed directly. The development of the central ner-
vous system is especially affected by certain mercury compounds,
known as teratogenic agents, which are toxic to the developing
neurological system (Young et al., 2008). However, the relationship
between mercury exposure and carcinogenesis (one of the most
serious outcomes of DNA-induced damage) is still debated, since
some experiments appear to show that mercury has genotoxic
activity, while others have not proven such DNA-damaging effects
(Fig. 2)(Crespo-López et al., 2009).
In yeast and animal cells, chromium’s genotoxicity and carcino-
genicity are being studied extensively. Those who work in the min-
ing and consuming sectors that use Cr have also been shown to be
at risk for cancer (Li Chen et al., 2012; Thompson et al., 2012).
Researchers found that Cr(VI) causes a wide range of genetic mate-
rial structural changes, including DNA chromosomal protein cross-
links, inter-DNA strand cross-links, and nucleotide strand breakage
in living and cultured cells (Fang et al., 2014).
5. Treatment options from natural resources
5.1. Neurotoxicity treatment
Taking into account Mn-related toxicity mechanisms and phar-
macokinetics, several therapeutic approaches, and neuroprotective
compounds have been investigated to evaluate their efficacy in
alleviating the Mn-induced neurotoxicity. Anti-inflammatory com-
pounds, natural and synthetic antioxidants, glutamate protectors,
and ATP/ADP ratio protectors have been used to decrease Mn-
induced neurotoxicity. Also, the efficacy and mechanisms of sev-
eral therapeutic interventions such as ethylene-diamine-tetra
acetic acid (EDTA), levodopa, and para-aminosalicylic acid (PAS)
have been established. An analysis with the polyphenolic extract
Euphorbia suppina (PPEES) from a Korean prostrate spurge has
shown that PPEES can effectively inhibit Mn-induced neurotoxicity
by antioxidants by modulation of endoplasmatic reticule (ER)
stress and ER stress-mediated apoptosis. The amounts of ROS and
malondialdehyde (MDA), which are products of lipid peroxidation,
were also significantly reduced. The antioxidant activities of GSH
and SOD and catalase (CAT) were enhanced at the same time.
Improvement of Mn-induced histopathological alterations in the
striatum and cerebral cortex by PPEES was also seen in vivo work
(Bahar et al., 2017). A research has shown that curcumin and
arsenic could substantially protect arsenic-induced dopaminergic
changes and oxidative stress in rat’s brain (Fig. 3). In another study,
Yousef et al. (2008) also found that carcinogen-induced metabolic
changes in the brain and liver of rats could be protected by cur-
cumin (Rahaman et al., 2021; Yousef et al., 2008). Aware of the fact
that the behavioral and neurochemical roles of brain biogenic ami-
S. Mitra, Arka Jyoti Chakraborty, Abu Montakim Tareq et al. Journal of King Saud University – Science 34 (2022) 101865
7

nes and NOs have a significant role to play, this research explores
the neuro-protective impact of curcumin against modifications of
the arsenic on biogenic amines, their metabolites and NO amounts
in rats (Yadav et al., 2010). A study demonstrates about a bio-
hazard which is known as cadmium. It is also known as a strong
neurotoxin. Nuts provide vital nutrients required to sustain human
brain function. Cadmium was delivered by mouth at a dosage of
50 mg/kg per week with or without almond and walnut supple-
mentation in rats. Cadmium-induced depression, anxiety and
memory decline were greatly attenuated by dietary consumption
of almonds and walnuts at a dosage of 400 mg/kg/day. Following
supplementation of certain nuts in rats, neurochemical aberrations
have stabilized. The current research indicates that long-term
almond and walnut supplementation provides vital nutrients that
can overcome dietary shortages and thereby decrease heavy-metal
intoxication (Batool et al., 2019). PCA has also stopped inflamma-
tion caused by Cd by minimizing cytokines, including tumor necro-
sis factor-
a
and interleukin-1b, pro-inflammatory. In comparison,
PCA supplementation relieved neuronal death caused by Cd by
increasing Bcl-2 and reducing cortical tissue levels of Bax and
Cas-3 (Al Olayan et al., 2020). A research investigated the potential
involvement in Tl(+) mediated toxicity of a glutamatergic portion
in rats by dizocilpine (MK-801) receptor through Nmethyl-d-
aspartate (NMDA). Early (24-hour) motor shifts, decreased Glu-
tathione (GSH) levels, lipid peroxidation, and GSH peroxidase
activity induced by Tl(+) acetate (32 mg/kg, ip) of adult rats were
examined for the effects in MK-801 (1 mg/kg, intraperitoneally
[ip]). In rat striatum, hippocampus or midbrain, the Tl(+)-induced
hyperactivity and lipid peroxidation were diminished, and mild
effects were generated at other endpoints (Osorio-Rico et al.,
2015). The effects of curcumin are antioxidant, anti-inflammatory
and antidepressant (Rahaman et al., 2021). The rescue function
for curcumin in Copper
2+
mediated toxicity of D. Melanogasters
was assessed in this report. For 7 days, Cu
2+
(1 mM) and/or Cur-
cumin (0.2 to 0.5 mg/kg Feed) is exposed to adult, wilderness flies
in the diet. The findings showed Cu
2+
- flies were less likely than the
control group to survive. Around the same time as the activity of
rising acetylcholinesterase, nitric oxide and Dopamine levels, the
toxicity of copper was also associated with a substantial decline
in overall Thiol (T-SH) as well as the catalase and glutathione S-
transferase activities. In addition, curcumin has restored the rates
of outbreak and the status of cellular antioxidants and alleviated
nitric oxide level accumulation in the fly. Curcumin has improved
oxidative damage to the flies, as shown by survival rates, durability
testing and antioxidant status restoration (Fig. 3)(Abolaji et al.,
2020). Apigenin is also used to treat copper induced neurotoxicity
(Dourado et al., 2020). The small dipeptide of carnosine (b-alanyl-
L-histidine) has many positive impacts, including preservation of
the acid-base balance, anti-glycemia, chelating agents, anti-
crosslinking and antioxidants. The skeletal muscle and the hip-
pocampus have elevated amounts of carnosine and its analog
anserine (1-methyl carnosine). In pathogenesis of vascular demen-
tia (VD), the neurotoxicity of zinc (Zn), caused by carnosine, plays a
key function, and inhibits neuronally-borne death by Zn. Lead (Pb)
is an all-encompassing pollutant for the atmosphere and for the
industry. It causes neurotoxicity and cell mortality by disturbing
pro- and anti-oxide balance; however, it is still not yet completely
known the mechanisms of its toxicity. The isoflavonoid genistein
(GEN) derived from soy has been reported to have neuroprotective
and antioxidant effects. The research explored the pathways for
in vivo and in vitro Pb-induced neurotoxicity to guard against
Pb-induced toxicity of GEN. Cell viability was decreased and
cell apoptosis was increased with the exposure of the Pb. In vitro
production of reactive oxygen species (ROS), and GEN pretreat-
ment significantly reduced Pb-induces oxidative injury by increas-
ing main antioxidant enzyme expression, nuclear factor 2 p45-
related, antioxidant transcription factor 2 (Nrf2). The activation
of the PKC-
a
in vitro and pretreatment PB attenuated ROS genera-
tion by PKC-
a
inhibition was then established following Pb expo-
sure and pretreatment. GEN also inhibited MAPK-NF-B activation
induced by Pb (Su et al., 2016). The levels of lipid permeation, pro-
tein carbonyl, ROS production were substantially increased by the
exposed rats to lead, and the activity in glutathione peroxidase,
superoxide dismutase, and catalase in the cerebellum and brain
cortex respectively decreased compared to controls. Abnormal
histopathology and a rise in blood and brain lead levels in contrast
with controls were also observed. The extent of lipid peroxidation,
the volume of protein carbonyl, the production of ROS and
Fig. 3. Diagrammatic explanation of heavy metal toxicity treatment by natural bioactive molecules.
S. Mitra, Arka Jyoti Chakraborty, Abu Montakim Tareq et al. Journal of King Saud University – Science 34 (2022) 101865
8

increased glutathione peroxidase, the superoxide dismutase and
catalase activity have been decreased and safety were shown in
histopathological tests (Kumar Singh et al., 2018).
5.2. Nephrotoxicity treatment
Chronic cadmium toxicity (Cd) is acquired by oral Cd adminis-
tration, causes serious damage to the kidneys. The histologic mod-
ifications triggered by Cd have been improved by curcumin
pretreatment. Urinary excretion substantially decreased from the
Molecules of Kidney Damage (KIM-1). Osteopontin (OPN), metallo-
proteinase 1 tissue inhibitor (TIMP-1), lipocaline associated neu-
trophil gelatinase (NGAL) and netrin-1. The use of curcumin has a
significant protective effect against nephrotoxicity caused by Cd
(Kim et al., 2018). The levels of renal function markers, lipid perox-
idation, renal injury molecules-1 (KIM-1), metallothionein,
interleukin-1b, tumor necrosis factor-i, nitric oxide, and apoptosis
regulators Bax and caspases-3 also increased significantly in the
renal tissues of royal-jelly treated mice, while antioxidant enzyme
activity, the levels of glutathione, and apoptosis inhibitor Bcl-2
were important (Fig. 3). Vacuation and congested glomeruli in
the kidney tissue of royal-jelly treated mouse is seen in histopatho-
logical tests (Almeer et al., 2019). Moreover, overall protein level
was decreased in the cadmium-induced toxicity which was
improved when treated with protocatechuic acid (Adefegha et al.,
2015).
A study demonstrates that silymarin and dimercaptosuccinic
acid reduce blood lead levels and provide protection against geno-
toxic effects (Alcaraz-Contreras et al., 2016). Besides, gamma-
glutamyl cysteine, piperine, and Spirulina platensis are also used
in this regard. To eradicate chromium induced nephrotoxicity Spir-
ulina platensis, eugenol, extra virgin olive oil and simvastatin are
usually used. A substantial decrease in MDA content and ACP activ-
ity and improved LDH and ALP activity relative to HgCl
2
treated
community was observed in comparison with spirulina with HgCl
2
.
Spirulina also greatly decreases pathological changes in the kid-
neys before and following treatment with mercury (Sharma
et al., 2007). Quercetin and L-
a
-Phosphatidylcholine also play vital
role in this context (Elblehi et al., 2019; Kim et al., 2014). Besides
these, diallyl sulfide and curcumin and zinc sulfate and silymarin
can eradicate thallium induced nephrotoxicity (Abdel-Daim and
Abdou, 2015; Al-jawad et al., 2017).
5.3. Carcinogenicity treatment
A recent study shows that sodium arsenite and DMA intensify
chronic exposure to the urinary bladder. The expression of the
metallopeptidase 9 matrix (MMP-9) and surviving are linked to
carcinogenesis. These biomarkers may be used to mark the medi-
ated carcinogenesis of the bladder. Oxidative damage that mini-
mizes carcinogenesis is minimized as a burden. MiADMSA may
be beneficial for blood carcinogenesis caused by systemic arsenic.
The data revealed that the tissue-arsenic content, ROS, TBARS level,
catalases, SOD activities (Islam et al., 2021) and GSH level, which
can induce an eighth OHdG rise, were dramatically enhanced by
sodium arsenite and DMA exposure. These improvements may
have improved pro-oncogenic biomarkers such as MMP-9 and
serum, bladder tissue, NBT-II and T-24 cells survived. In NBT-II
and T-24 arsenic-exposed cells, a high cell migration and clono-
genic ability indicate important carcinogens. In MiADMSA therapy,
substantial recuperation was observed in these biomarkers (Sathua
et al., 2020). Another study demonstrates that the levels of
lead mediated hepatic and renal damage products and lipid perox-
idation have been greatly suppressed prior to therapy using extract
of Rosmarinus officinalis.Rosmarinus officinalis has also retained the
composition and renal and hepatic cells in blood cells (Mohamed
et al., 2016). Cd increased dose-dependent proliferation of lines
of ovarian cancer cells. Cd-induced OVCAR3 and SKOV3 cell lines
were blocked by melatonin. In addition, CdCl2 increased dramati-
cally ER
a
expression compared with control in both the OVCAR3
and SKOV3 cell lines. Cd induction effect on ER
a
expression of
OVCAR3 and SKOV3 cells was substantially inhibited by mela-
tonins. In conclusion, Cd may have a significant role in the etiology
of ovarian cancer by developing cells of ER
a
expression because of
the proliferative effect on the lines of cancer in the ovary (Ataei
et al., 2018). Besides, piperine, curcumin, beta-cryptoxanthin and
sulforaphane can help in this regard (Liu et al., 2016; Mohajeri
et al., 2017; Verma et al., 2020; Wang et al., 2018b). Quercetin pro-
tects against nickel-induced hepatic dysfunction, elevates the his-
tology modifications in the liver of nickel, decreases the expression
of inflammatory markers in nickel exposed livers of mice,
decreased the overall DNMT activity and Nrf2 DNA methylation
of nickel exposed livers of the rat, and reduced carcinogenicity
(Fig. 3)(Liu et al., 2015). Metformin is another candidate for treat-
ing nickel-induced carcinogenicity (Kang et al., 2017).
5.4. Hepatotoxicity treatment
Salidroside (SDS) shows clear antioxidant activity and can treat
lead acetate-induced liver damage by reducing oxidative stress and
boosting antioxidant stress activity, therefore improving liver tis-
sue structure. In this approach, it is possible to eliminate lead-
induced hepatotoxicity (Chen et al., 2019). Furthermore, berberine
was discovered to raise serum albumin, reducing lead-induced
hepatotoxicity (Hasanein et al., 2017; Rauf et al., 2021). Carnosine,
curcumin, and thymoquinone also significantly reduced lead-
related histological and hepatological complications (Fig. 3). In a
research, selenium (Se) was found to be an efficient chemo-
protectant of Cd. Se therapy was shown to significantly reduce
Cd-induced hepatocyte mortality and morphological changes.
Simultaneously, Se decreased ROS generation, increased reduced
glutathione (GSH) levels, and increased selenoenzyme (glutathione
peroxidase, GPX) activity, all of which helped to attenuate Cd-
induced oxidative stress. Finally, it was discovered that Se may
protect against Cd-induced hepatotoxicity by inhibiting the ER
stress response (Zhang et al., 2020). In another study, the impact
of M. oleifera-based diets on nickel (Ni)-induced hepatotoxicity in
rats was investigated. Male rats were divided into six groups and
administered 20 mg/kg body weight nickel sulfate in normal saline
before being fed either a standard diet or an M. oleifera-based diet
for 21 days. All of the animals were anesthetized and killed 24 h
following the final treatment. The activities of alanine transami-
nase, aspartate transaminase, and alkaline phosphatase in rat
plasma were considerably increased after exposure to nickel. Ni
also increased triglyceride, total cholesterol, and low-density
lipoprotein cholesterol levels while lowering high-density lipopro-
tein cholesterol levels. Furthermore, Ni exposure increased rat
plasma malondialdehyde while depleting glutathione levels. The
histopathology findings indicated that Ni exposure induced inflam-
mation and cellular damage. M. oleifera-based diets were shown to
protect rats against Ni-induced hepatotoxicity by increasing liver
function indicators, lipid profile, and restoring cellular architecture
and integrity.
5.5. Immunological toxicity treatment
Pterostilbene (PT) is a naturally occurring chemical found
mostly in blueberries. PT has been shown in studies to be an effec-
tive anti-inflammatory and anti-oxidant agent. Epidermal Cr(VI)
delivery produced cutaneous inflammation in mice ear skin in an
in vivo investigation, and pro-inflammatory cytokines TNF-
a
and
IL-1 were identified in the epidermis, indicating a level of rise fol-
S. Mitra, Arka Jyoti Chakraborty, Abu Montakim Tareq et al. Journal of King Saud University – Science 34 (2022) 101865
9

lowing Cr(VI) therapy. Meanwhile, the findings of another in vitro
experiment revealed that treatment of HaCaT cells with varying
doses of Cr(VI) promoted apoptosis and endoplasmic reticulum
(ER) stress (human keratinocyte). Cr(VI) triggered the p38
mitogen-activated protein kinase (MAPK)/MAPK-activated protein
kinase 2 (MK2) pathways, which elevated TNF-
a
and IL-1 mRNA
expression. In the epicutaneous elicitation test, the intensity of
the skin responses was dramatically reduced when the mouse
was given PT. In addition, PT treatment reduced inflammation
and apoptosis in HaCaT cells in vitro. Furthermore, recent studies
revealed that the NLRP3 inflammasome may be implicated in Cr
(VI)-mediated apoptosis and inflammation in allergic contact der-
matitis (ACD) (Wang et al., 2018a). Besides, nuclear factor
(erythroid-derived 2)-like 2 (Nrf2) attenuated autoimmunological
problems induced by chromium (Banerjee et al., 2020). In combi-
nation with Se, myo-inositol protects mice from Cd-induced thy-
roid injury. When utilizing the follicular structure as a read-out
for comparison, the effectiveness of this combination was larger
than that of resveratrol (Benvenga et al., 2020). In another study,
curcumin (diferuloylmethane), a natural substance derived from
the rhizomes of Curcuma longa, was evaluated in a guinea pig
model of airway hyper responsiveness for its anti-asthmatic prop-
erties. Curcumin was given to guinea pigs during sensitization (to
see whether it may prevent airway obstruction) or after they had
symptoms of airway obstruction (to examine its therapeutic
effect). Specific airway conductance (SGaw) was measured using
a non-invasive method called constant-volume body plethysmog-
raphy to detect the status of airway constriction and hyper reactiv-
ity. OVA-induced airway constriction (p=0.0399) and airway hyper
reactivity (p=0.0043) are dramatically reduced when curcumin
(20 mg/kg body weight) is given. Curcumin is useful in correcting
defective airway characteristics in OVA-sensitized guinea pigs,
according to the findings (Ram et al., 2003).
5.6. Cardiovascular toxicity treatment
Mercury and cadmium are very hazardous elements that may
cause serious cardiac problems in both animals and humans. In a
study, the therapeutic impact of vitamin C against these metals
in rabbits was investigated, and favorable findings for heart toxic-
ity were discovered (Ali et al., 2020). In another study, the histolog-
ical and biochemical alterations detected in the rat heart after
exposure to K
2
Cr
2
O
7
were greatly reduced when the rats were
given C. aurantium peel extract (300 mg/kg). Because of its antiox-
idant activity, C. aurantium peel extract was able to prevent
K
2
Cr
2
O
7
-induced myocardial damage, according to their findings
(Chaabane et al., 2017). A recent study demonstrates that oxidative
stress, hematological changes, structural disorder, cardiomyocyte
apoptosis, and heart malfunction, caused by K
2
Cr
2
O
7
were all
reduced by Sulforaphane (SFN). SFN decreased the levels of p53,
cleaved Bcl2-associated X protein, caspase-3, interleukin-1, and
nuclear factor kappa-B, while increasing the levels of Sesn2, NAD
(P)H quinone oxidoreductase-1, heme oxygenase-1, nuclear factor
erythroid 2-related factor 2 (Nrf2), and phosphorylated adenosine
5
0
-mon. The Sesn2/AMPK/Nrf2 signaling pathway is activated by
SFN, which reduces Cr(VI)-induced cardiotoxicity. SFN might be a
potential therapeutic for chronic Cr(VI) exposure as well as a
defender against Cr(VI)-induced cardiac impairment (Yang et al.,
2020).
5.7. Skin toxicity treatment
Research was conducted to explore if Solanum melongena peel
extract could help with arsenic-induced Bowen’s disease. From
the two arsenic-endemic sites, a total of eight individuals with
arsenic-induced Bowen’s illness were chosen. Each patient was
given a peel extract containing ointment and advised to apply it
twice daily on the lesion site for 12 weeks. Significant improve-
ment was observed in reducing the lesion of Bowen’s disease
(Sarah and Misbahuddin, 2018). In another research, PUVA therapy
was used to treat two male patients who had long-term contact
sensitivity to chromium. One patient with simultaneous photosen-
sitivity had a very positive response; his skin lesions cleaned up
and his light tolerance improved. On PUVA-exposed (pigmented)
skin, this was accompanied by a reduction in photopatch test reac-
tivity and the extinction of patch-test reactivity. In both cases,
PUVA therapy reduced the amount of rosette-forming T cells while
increasing lymphocyte stimulation. While PUVA-therapy may have
some systemic immunological effects, it appears that its abating
impact on contact sensitivity and photosensitivity is mostly medi-
ated through local mechanisms in the skin (Jansén et al., 1981).
Besides, Epigallocatechin-3 gallate is used to treat acne vulgaris
(Yang et al., 2017).
5.8. Reproductive and developmental toxicity treatment
A recent study demonstrated the importance of grape seed
proanthocyanidin extract which reduced oxidative stress damage
in mouse testis, counteracting arsenic-induced reproductive toxic-
ity by activating Nrf2 signaling (Li et al., 2015). Another study
investigated the impact of lutein over arsenic-induced reproduc-
tive toxicity. The findings revealed that lutein reduces arsenic-
induced reproductive toxicity in male mice via Nrf2 signaling, indi-
cating a plausible mechanism for lutein in avoiding reproductive
harm and elucidating that ingesting lutein-rich plant sources can
reduce chemical-induced reproductive toxicity (Li et al., 2016b;
Mitra et al., 2021b).
A considerable rise in tissue indicators of oxidative stress, sev-
ere histopathological alterations, seminal tubule destruction, poor
sperm parameters, low spermatogenesis index, tubular desquama-
tion, and decreased sperm mitochondrial function were all signs of
lead poisoning in the reproductive system. In the rat reproductive
system, carnosine and histidine supplementation reduced lead-
induced oxidative stress and mitochondrial dysfunction. Carnosine
and histidine’s antioxidative and mitochondria-protective capabil-
ities thus act as main defense mechanisms against lead-induced
reproductive damage (Ommati et al., 2019). Male reproductive
protection was demonstrated by reduced Pb-induced testicular
injury, higher sperm count and motility, and a lower sperm abnor-
mality rate. Anthocyanin from purple sweet potato (APSP) also
helps in Pb-induced decreases in enzymatic and non-enzymatic
antioxidants. Furthermore, APSP inhibited Pb-induced Bax mRNA
and protein expression, decreased caspase-3 activation, increased
Bcl-2 protein expression, and avoided DNA damage caused by Pb.
Pb-induced testicular JNK signaling was similarly disrupted by
APSP administration, which inhibited Jun N-terminal kinase (JNK)
mRNA expression and phosphorylation, leading in c-Jun expression
suppression. Pb was able to reverse the effects of APSP. Finally,
because of its antioxidant and anti-apoptotic characteristics, as
well as its regulation of the JNK signaling pathway, APSP may be
a viable therapeutic treatment for avoiding Pb-induced reproduc-
tive damage (Zhou et al., 2021).
5.9. Genotoxicity treatment
Arsenic is a well-known genotoxicant that creates an overabun-
dance of reactive oxygen species (ROS) and inhibits antioxidant
enzyme systems, resulting in cell damage via the activation of
oxidative sensitive signaling pathways. Green tea’s primary
polyphenolic catechin, epigallocatechin gallate (EGCG), has shown
significant antioxidant, free radical scavenging, and genoprotective
activities in vivo. By controlling arsenic-induced oxidative stress in
S. Mitra, Arka Jyoti Chakraborty, Abu Montakim Tareq et al. Journal of King Saud University – Science 34 (2022) 101865
10

mice, the researchers intended to examine the antioxidant and
genoprotective effectiveness of EGCG. For 15 days, animals were
given prophylactic and therapeutic dosages of EGCG (25 and
50 mg/kg b.wt.) orally, and then arsenic was delivered intraperi-
toneally at a dose of 1.5 mg/kg b.wt. (1/10th of LD50) for 10 days.
Increased ROS production (114%) in lymphocytes; increased levels
of LPO (2–4 fold); reduced levels of hepato-renal antioxidants (ap-
prox. 45%) and augmented genomic fragmentation in hepato-renal
tissues; increased chromosomal anomalies (78%) and micronucle-
ation (21.93%) in bone marrow cells; and comet tailing (25%) in
lymphocytes of mice after arsenic intoxication (Kaushal et al.,
2019). Researchers explored if curcumin nanoformulations might
protect against arsenic-induced genotoxicity better than free cur-
cumin. The emulsion process was used to make curcumin-loaded
poly(lactic-co-glycolic acid) nanoparticles (CUR-NP). The CUR-NP
was water soluble and released in two phases. The rats were placed
into five groups, each with six rats. Chromosome abnormalities,
micronuclei production, and DNA damage were all exacerbated
by arsenic. Both free curcumin and CUR-NP reduced the genotoxic
effects of arsenic. However, at the same dosage level, the results
imply that nanoformulations has a better protective impact than
free curcumin (Sankar et al., 2014).
Researchers looked examined how silymarin and dimercapto-
succinic acid (DMSA), a chelating agent, worked against lead (Pb)
poisoning in rats whether given singly or in combination. Wistar
rats (n = 200) were put into five groups at random. Group A was
used as a control group. For 8 weeks, groups B–E were exposed
to 2000 ppm of lead acetate in their drinking water. A positive con-
trol group, Group B, was used. For 8 weeks, Group C was given sily-
marin (100 mg kg
1
orally). For the final 5 days of therapy, Group D
got DMSA (75 mg kg
1
orally) once daily. Groups C and D were
given DMSA and silymarin, respectively. The impact of Pb was
assessed, and therapies were estimated based on blood lead levels
(BLLs), renal system, and genotoxic effects using the comet assay.
Following exposure to lead acetate, the BLLs considerably
increased. BLLs were reduced after silymarin and DMSA were
administered. Silymarin and DMSA were found to give consider-
able protection against Pb’s genotoxic effects (Alcaraz-Contreras
et al., 2016). The experimental evidences regarding the treatment
options for heavy metal induced toxicities are highlighted in
Table 1.
6. Nanotechnological and nanomedicinal approaches to treat
heavy metal toxicity
The use of nanotechnology for heavy metal analysis and
removal from water and food is on the rise. Heavy metal removal
has been accomplished via the use of a number of nanomaterials,
including metal oxide nanoparticles, graphene and its derivatives,
magnetic nanoparticles (MNPs), and carbon nanotubes (CNTs), to
name a few. Using nanotechnology for heavy metal analysis and
removal from food and water resources offers many benefits over
traditional methods. These advantages include a broad linear
range, low detection and quantification limits, a high sensitivity,
and excellent selectivity. There is a need for nanotechnology-
based methods to be used in the field in a simple and safe manner
(Gong et al., 2021).
The elimination of heavy metals by metal oxide nanoparticles,
MNPs, graphene, its oxides and its derivatives, CNTs, and other
nanomaterials will be discussed in the following sections:
6.1. Metal oxide nanoparticles
Metal oxide nanoparticles have been used in the removal of
hazardous heavy metal ions from contaminated water as a result
of their unique physical and chemical characteristics. Recent years
have seen the development of green chemical methods for the pro-
duction of magnetic nano adsorbents, which include natural
biopolymers and biological wastes. These methods have been
developed because of their low cost and high availability, as well
as their biodegradability and strong affinity for metal capping
(Bayat et al., 2015).
CuO with a variety of structural variations was synthesized at
the nanoscale, and it shown excellent adsorption characteristics
for As
3+
, As(V), Pb
2+
, and Cr(VI). In this study, CuO nanoparticles
with a high specific surface area and a homogeneous particle size
distribution were created using the cold finger aided magnetron
sputtering method. CuO nanoparticles with a significant adsorp-
tion influence on heavy metal ions were found to be produced. It
is possible to increase the adsorption site and surface area of
CuO in order to enhance the adsorption capacity of the material.
The alteration of CuO’s structure at the nanoscale increases the
number of active sites for metal ions, which plays an important
role in the removal of heavy metal ions from the environment
(Gupta et al., 2016).
Environmental concerns produced by the Cr
3+
ion can be
addressed in a novel manner by the production of SiO
2
mesoporous
nanoparticles with organic surfactants. Organo-silica mesoporous
materials containing cyano functional groups were made utilizing
a one-pot co-condensation of 2-cyanoethyltriethoxysilane and
tetraethoxysilane at 1:4 and 1:9 ratios, respectively, using sun-
flower oil or n-dodecyl amine as templating agents. The cyano
group was utilized as an adsorption site, and the carboxyl surface
functional group was hydrolyzed to form carboxyl surface func-
tional group. The removal rate of the Cr
3+
ion ranges from 48 to
83% depending on the functional groups of the adsorbents used,
and the ratio of silicone to silica in the mixture. Results showed
that the produced material is an excellent adsorbent (Gervas
et al., 2016).
6.2. Magnetic nanoparticles
Surface coatings on magnetic Fe
3
O
4
nanoparticles are often
used to (1) prevent aggregation and oxidation and (2) improve
selectivity to particular targets. For example, a core–shell structure
composed of a core of Fe
3
O
4
, a shell of SiO
2
, and a shell of polythio-
phene has been described. It may be used to separate and enrich
Hg
2+
ions in a variety of matrices quickly (Abolhasani et al.,
2015). Another example is Fe
3
O
4
hybridized with polyaniline and
MnO
2
(Fe
3
O
4
/PANI/MnO
2
)(Cao et al., 2016; Ma et al., 2013), which
can be produced economically and in a green way while exhibiting
a high capacity for the adsorption of heavy metal ions (including
Pb
2+
,Zn
2+
,Cd
2+
, and Cu
2+
)(Zhang et al., 2017).
Poly-(m-phenylenediamine) (PmPD), an amino-conjugated
polymer, has a high concentration of amine and imine functional
groups, which enhances its redox performance, chelating ability,
and adsorption capacity. PmPD and PANI are structurally and func-
tionally identical. As a result, adding MnO
2
to PmPD is theoretically
possible. Due to its high adsorption capacity and intrinsic param-
agnetic characteristic, the MnO
2
/Fe
3
O
4
/PmPD core–shell hybrid
enables the separation and removal of heavy metal contaminants
on a wide scale via ion exchange, electrostatic attraction, and coor-
dination interaction (Xiong et al., 2020).
Nano-zerovalent iron (NZVI) also has excellent repairing capa-
bilities and is inexpensive to produce, making it a promising mate-
rial for the future. It has been shown that adsorbing and purifying
hazardous contaminants, particularly inorganic ions and heavy
metal ions, is feasible (Dong et al., 2016; Shi et al., 2011). On the
other hand, NZVI is oxidized when exposed to oxygen, air, or water,
resulting in a decrease in reactivity. Because nickel ions are more
stable than iron ions, they may be used to slow down the oxidation
S. Mitra, Arka Jyoti Chakraborty, Abu Montakim Tareq et al. Journal of King Saud University – Science 34 (2022) 101865
11

Table 1
Treatment options for heavy metal induced toxicities.
Field of Study Treatment
for
Treatment procedure/
element
Study model Dose Assay Outcomes References
Heavy Metal-induced
neurotoxicity
Manganese Polyphenolic extract of
Euphorbia supina
(PPEES)
Human
neuroblastoma
SKNMC cells
and SD male
rats
(50, 100 and
200 mg/mL)
Western blot and RT-PCR
analyses
PPEES significantly increased the cell viability and decreased LDH
activity of Mn-exposed cells, which could protect the SKNMC cell
from cytotoxicity
(Bahar et al.,
2017)
Para-amino salicylic
acid (PAS)
Female aged 50 6 g n.m. Symptoms were significantly alleviated, and handwriting recovered
to normal
(Jiang et al.,
2006)
Arsenic Curcumin Rats 100 mg/kg Reversed phase HPLC and
electrochemical detector
Significant increase in the levels of DOPAC (30%), 5-HT (70%), DA
(42%), and HVA (50%) in corpus striatum as compared to those
treated with arsenic alone
(Yadav et al.,
2010)
Gallic acid Sprague Dawley
male rats (36)
Saline + GA
(50 mg/kg/mL)
Elevated plus maze, Light
dark activity box, Forced
swim test and Morris water
maze
Increased brain LP, brain antioxidant enzymes activity, brain
acetylcholinesterase activity
(Samad et al.,
2019)
Saline + GA
(100 mg/kg/mL)
iAS + saline
iAS + GA (50 mg/
kg/mL)
iAS + GA
(100 mg/kg/mL)
iAS
Cadmium Almond and walnut Rats 400 mg/kg/day Elevated plus maze, novel
object recognition task, and
Morris water maze
Attenuated depression, paranoia and impairments in memory due
to cadmium.
(Batool et al.,
2019)
Protocatechuic acid Adult male
Wistar rats
100 mg/kg ELISA kits Cd concentration decreased dramatically and activity of cortical
acetylcholinesterase and neurotropic factor derived from the brain
increased
(Al Olayan
et al., 2020)
Melatonin Mouse
neuroblastoma
cells (Neuro-2a
cells)
12.5, 25 and
50
l
M
CTSB activity fluorometric
assay
Increased ‘‘TFEB-responsive genes”, preserved lysosomal protease
activity, maintained the lysosomal pH level, enhanced
autophagosome-lysosome fusion
(M. Li et al.,
2016)
Thallium MK-801 Rats