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Occupational Diseases and Environmental Medicine, 2019, 7, 144-163

https://www.scirp.org/journal/odem

ISSN Online: 2333-357X

ISSN Print: 2333-3561

DOI:

10.4236/odem.2019.74012 Oct. 17, 2019 144

Occupational Diseases and Environmental Medicine

Cadmium Toxicity: Oxidative Stress,

Inflammation and Tissue Injury

Sandra Concepcion Das

1,2*

, Hamda A. Al-Naemi

1,2*

Laboratory Animal Research Center, Qatar University, Doha, Qatar

Department of Biological & Environmental Sciences, Qatar University, Doha, Qatar

Abstract

Cadmium is a known environmental pollutant targeting various organs. Of-

ten implicated in cadmium toxicology is the formation of reactive oxygen

species, overwhelming the free radical scavenging mechanisms and inducing

oxidative stress. Acute cadmium intoxication has been shown to reduce anti-

oxidant enzyme activity and induce oxidative stress. However, chronic intox-

ication has obscure outcomes in oxidative stress while the cell makes adjust-

ments to overcome the toxicant load. Also linked with the occurrence of

oxidative stress is inflammation. Stimulation of acute or chronic inflamma-

tion is mediated by different cascades. However, key events include activation

of transcription factor, NF-

B and release of pro-

inflammatory cytokines.

Both oxidative stress and inflammation are implicated simultaneously in pa-

thogenesis and induction of multi-organ tissue damage under cadmium ex-

posure. This article reviews the impact of acute and chronic cadmium intoxi-

cation on inducing oxidative stress, inflammation and thereby inflicting tis-

sue damage.

Keywords

Cadmium, Inflammation, Tissue Injury

1. Cadmium as an Environmental Pollutant

Cadmium is naturally occurring element in the Earth’s crust with concentrations

of 0.1 - 0.5 ppm in association with ores of zinc, lead and copper. It is a heavy

metal that has various industrial applications with about 24,000 metric tons be-

ing produced yearly worldwide [1]. This production mainly caters to the manu-

facturing of nickel-cadmium batteries, pigments, chemical stabilizers, metallic

coatings and alloys. In the environment, Cd is derived naturally and anthropo-

How to cite this paper:

Das,

S.C. and

-Naemi, H.A. (2019)

Cadmium Toxicity:

Oxidative Stress, Inflammation and Tissue

Injury

Occupational Diseases and Env

ronmental

Medicine

, 144-163.

https://doi.org/10.4236/odem.2019.74012

Received:

August 25, 2019

Accepted:

October 14, 2019

Published:

October 17, 2019

9 by author(s) and

Scientific

Research Publishing Inc.

This work is licensed under the Creative

Commons Attribution International

License (CC BY

4.0).

http://creativecommons.org/licenses/by/4.0/

Open Access

S. C. Das, H. A. Al-Naemi

DOI:

10.4236/odem.2019.74012 145

Occupational Diseases and Environmental Medicine

genically, frequently circulating between three environmental compartments of

the air, water and soil. A contributing factor to its circulation in the environ-

mental compartments is its high persistence due to non-biodegradability. Addi-

tionally, the metal is reported to have a high rate of transfer from soil-to-plant,

making it possible for Cd to enter the food chain [2].

Cadmium is considered to be a xenobiotic metal as it is known to be toxic to

plants, animals and humans even at low concentrations and has no essential bi-

ological functions [3]. Owing to its ubiquity, toxicity and long biological half-life

(ranging between 10 - 35 years) [4], its rising levels in the environment are cause

for public health concern. For humans, Cd can enter the body by inhalation of

tobacco smoke, ingestion of contaminated food and water, dermal absorption

and occupational exposure. For non-occupationally exposed and non-smokers,

the main route of exposure is via ingestion of Cd-contaminated food and water.

The route of exposure impacts Cd absorption wherein inhalation contributes of

up to 50%, ingestion contributes to an estimated 10% and is nearly negligible by

dermal contact [5]. The ingested amount can increase up to 20% based on the

nutritional status of the individual [4]. Despite its industrial importance, recent-

ly, it is recognized as one among the 126 priority pollutants [6], a Class I carci-

nogen [7] and is considered an environmental pollutant and health toxicant [5]

[8].

Tissue Cd concentrations

vary based on the route, duration and dose of expo-

sure. The primary sinks of Cd body burden are stored in the kidney and liver

ranging from 50% - 85% out of which 30% - 60% is stored in the kidney alone.

Recently, it has been estimated that dietary Cd exposure contributed to 0.2% of

the global burden of chronic kidney disease [9]. Apart from the primary stores,

Cd-induced damage

has also been reported in brain [10], cardiovascular system

[11] [12], nervous system [13], immune system [14], gut [15] and reproductive

system [16] [17]. In addition to its ability to bioaccumulate, a relatively small

fraction (0.007%) of Cd is excreted from the body as urine and feces [4]. A well

cited epidemiological example of Cd-induced intoxication is the case of the

“Itai-itai” disease in Japan first identified in the 1960s and Cd-associated mortal-

ity is reported till date [18]. Various reviews discuss the oxidative mechanisms

and the inflammatory properties of incited by Cd exposure separatelyhowever

there is accumulating evidence of the interplay between oxidative stress and in-

flammation [19] [20] [21]. This review aims to provide an overview on the link

between Cd-induced oxidative stress, Cd-induced inflammation while discussing

its association with inflicted tissue injury as a result of Cd toxicity.

2. Cadmium-Induced Oxidative Stress

Pathologies of Cd intoxication has been associated with promoted oxidative

stress [22]. Oxidative stress is characterized by an imbalance in the production

of oxidants and antioxidants in the organ or the organism, favoring the former

and causing cellular disruption [23]. It has been discussed that this imbalance

may be a result of either overproduction of reactive oxygen species (ROS) and

S. C. Das, H. A. Al-Naemi

DOI:

10.4236/odem.2019.74012 146 Occupational Diseases and

Environmental Medicine

reactive nitrogen species (RNS) or weakening of the elimination of ROS by the

oxidant defense mechanisms [24]. However, physiological amounts of ROS are

required for normal cellular functions such as signal transduction, cell prolifera-

tion, gene expression and immune defense. Reactive oxygen species consist of

various amounts of hydrogen peroxide (H

), hydroxyl radical (HO•), supe-

roxide anions (

−

), peroxyl (RO•) and alkoxyl radicals (ROO•) whereas reac-

tive nitrogen species (RNS) include nitric oxide radical (NO•), nitrogen dioxide

radical (NO

•) and peroxynitrite (ONOO

−

). Under normal physiological condi-

tions, generation and elimination of these radicals are maintained under redox

balance.

Redox homeostasis is mediated via Nrf2 and NF-

B translocation [25], and

enzymatic and non-enzymatic antioxidant defenses [26]. Enzymes of the anti-

oxidant system that protect against ROS are superoxide dismutase, catalase and

glutathione peroxidase (

Figure 1). One of the main antioxidant enzymes is su-

peroxide dismutase (SOD) which is a metallo-enzyme found in the mitochon-

dria and cytosol that catalyze the conversion of oxygen radicals to hydrogen pe-

roxide, H

at a high reaction rate [26] [27]. The hydrogen peroxide produced

as a result of SOD activity is detoxified by catalases and glutathione peroxidases.

Catalases (CAT) are heme-containing enzymes that catalyze the breakdown of

into water and divalent oxygen. CAT activity is mainly localized in perox-

isomes and in a lesser extent in the cytoplasm of erythrocytes, in the nucleus and

Figure 1. Illustration showing the reactions to maintain redox balance in the cells. Free

radicals like superoxide anions generated by endogenous or exogenous sources is con-

verted to hydrogen peroxide by superoxide dismutase (SOD). The hydrogen peroxide is

further broken down to water and molecular oxygen by either catalase (CAT) or gluta-

thione peroxidase (GSH-Px). Glutathione reductase (GR) and GSH-Px work together to

maintain a balance in glutathione (GSH) and its reduced product (GSSG). The presence

of cadmium in cells interferes with these reactions by decreasing SOD,GSH and CAT

thereby producing OH radicals by Haber-Weiss and Fenton reactions and accumulating

free radicals. Hence, inducing oxidative stress. (Created using biorender.com).

S. C. Das, H. A. Al-Naemi

DOI:

10.4236/odem.2019.74012 147

Occupational Diseases and Environmental Medicine

in the mitochondria. While CAT is active in severe stress conditions, peroxidases

(Px) are suggested to protect the cell during acute oxidative stress. Unlike CAT,

Px detoxify H

through the oxidation of other organic substrates. Glutathione

peroxidases (GSH-Px) utilizes H

to oxidize GSH to glutathione disulfide

(GSSG). Another enzyme involved in the antioxidant defense system is gluta-

thione reductase (GR) which reduces GSSG to GSH. Both GSH-Px and GR work

together in the cells to maintain a steady state in the ratio of GSH to GSSG [28].

When the cells are under oxidative stress, the enzymes of the antioxidant defense

system respond by altering their activity to overcome the oxidative stimuli.

When the concentration of ROS exceeds the threshold such that it is not con-

trolled by antioxidants like ascorbic acid and glutathione or radical scavenging

enzymes like catalase, peroxidase and superoxide dismutase, oxidative damage

to various biomolecules (proteins, lipids and DNA) may ensue consequently

leading to cytotoxicity and genotoxicity [29]. Apart from the enzyme index, a

key measure of oxidative stress is lipid peroxidation, as indicated by the concen-

trations of malondialdehyde (MDA), which may accumulate as a result of cell

damage [30].

In response to Cd exposure, depending on the route of exposure various cel-

lular defense mechanisms are activated to overcome the toxic effects of Cd.

Among the main defense mechanisms are the induction of metallothionein

(MT) primarily in the kidney and liver, elevation in cellular glutathione and ac-

tivation of antioxidant transcription factor Nrf2. These mechanisms are not

“mutually exclusive” but may work together in a cohesive way to resist

Cd-induced oxidative stress. Following exposure, Cd enters the blood stream via

erythrocytes or albumin and undergoes hepatic conjugation where it complexes

with MT to form Cd-MT which can be filtered out by the glomerulus, reab-

sorbed at the proximal tubule and distal tubule. After its entry into the tubular

cell, lysosomes break the Cd-MT complex to free Cd. This free Cd initiates

damage to the kidneys consequently inducing oxidative stress. Apart from this

free Cd, ROS can also be produced when Fenton metals (like iron and copper)

are displaced by Cd from MT or through the depletion of GSH [27]. Highly ab-

undant in cells, GSH is a target of free Cd ions. Cd-induced depletion of the re-

duced GSH pool leads to the disruption of the redox balance leading to an oxid-

ative environment. Hence, Cd-induced oxidative damage is considered to be a

major mechanism rendering its toxicity to various organs by weakening the an-

tioxidant mechanism.

Cadmium does not induce ROS production directly however, this xenobiotic

metal could generate free radicals indirectly [27] [31]. The ensuing response to

the oxidative stress is dependent on the duration of exposure – acute or chronic.

In the case of acute Cd exposure, free radicals inclusive of superoxide anion, hy-

drogen peroxide, hydroxy radical and lipid radicals are generated. These

Cd-induced generation of free radicals are mediated by indirect mechanisms

such as depletion of glutathione, activation of Kupffer cells, inflammation and

involvement of iron in the Fenton reactions [24] [32] [33]. However, in chronic

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