Cellular mechanisms of cadmium induced toxicity: a review

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Cellular mechanisms of cadmium induced toxicity: a review
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  This article was downloaded by: [Manu Pant]On: 14 October 2013, At: 20:23Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registeredoffice: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK International Journal of EnvironmentalHealth Research Publication details, including instructions for authors andsubscription information:http://www.tandfonline.com/loi/cije20 Cellular mechanisms of cadmium-induced toxicity: a review Anju Rani a , Anuj Kumar b , Ankita Lal a  & Manu Pant aa  Department of Biotechnology, Graphic Era University, Dehradun,India b  JCDM College of Pharmacy, Sirsa, IndiaPublished online: 11 Oct 2013. To cite this article:  Anju Rani, Anuj Kumar, Ankita Lal & Manu Pant , International Journal of Environmental Health Research (2013): Cellular mechanisms of cadmium-induced toxicity: a review,International Journal of Environmental Health Research To link to this article: http://dx.doi.org/10.1080/09603123.2013.835032 PLEASE SCROLL DOWN FOR ARTICLETaylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis,our agents, and our licensors make no representations or warranties whatsoever as tothe accuracy, completeness, or suitability for any purpose of the Content. Any opinionsand views expressed in this publication are the opinions and views of the authors,and are not the views of or endorsed by Taylor & Francis. The accuracy of the Contentshould not be relied upon and should be independently verified with primary sourcesof information. Taylor and Francis shall not be liable for any losses, actions, claims,proceedings, demands, costs, expenses, damages, and other liabilities whatsoever orhowsoever caused arising directly or indirectly in connection with, in relation to or arisingout of the use of the Content.This article may be used for research, teaching, and private study purposes. Anysubstantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions  Cellular mechanisms of cadmium-induced toxicity: a review Anju Rani a  *, Anuj Kumar   b , Ankita Lal a  and Manu Pant  a  a  Department of Biotechnology, Graphic Era University, Dehradun, India;  b  JCDM College of   Pharmacy, Sirsa, India (  Received 21 March 2013;  󿬁 nal version received 30 June 2013 )Cadmium is a widespread toxic pollutant of occupational and environmental concern because of its diverse toxic effects: extremely protracted biological half-life(approximately 20  –  30 years in humans), low rate of excretion from the body andstorage predominantly in soft tissues (primarily, liver and kidneys). It is an extremelytoxic element of continuing concern because environmental levels have risen steadilydue to continued worldwide anthropogenic mobilization. Cadmium is absorbed insigni 󿬁 cant quantities from cigarette smoke, food, water and air contamination and isknown to have numerous undesirable effects in both humans and animals. Cadmiumhas a diversity of toxic effects including nephrotoxicity, carcinogenicity, teratogenic-ity and endocrine and reproductive toxicities. At the cellular level, cadmium affectscell proliferation, differentiation, apoptosis and other cellular activities. Current evidence suggests that exposure to cadmium induces genomic instability throughcomplex and multifactorial mechanisms. Most important seems to be cadmiuminteraction with DNA repair mechanism, generation of reactive oxygen species andinduction of apoptosis. In this article, we have reviewed recent developments and 󿬁 ndings on cadmium toxicology. Keywords:  cadmium; oxidative stress; apoptosis; metallothionein; DNA repair  Introduction Progressive industrialization in developing countries is currently evident. Industrial revo-lution leads to increasing global metal pollution and increasing production andconsumption of heavy metals including cadmium (Flora et al. 2008). About 13,000 tonsof cadmium (Cd) is produced yearly worldwide, mainly from nickel-cadmium batteries, pigments, chemical stabilizers, metal coatings and alloys (Table 1). Although emissionsin the environment have markedly declined in most industrialized countries, Cd remainsa source of concern for industrial workers and for populations living in polluted areas,especially in less-developed countries (Sun et al. 2006; Govil et al. 2007; Bernard 2008). In industries, Cd is hazardous both by inhalation and ingestion and can causeacute and chronic intoxications. It has been found that cadmium largely contributes tothe contamination of agricultural land. Cadmium is selectively taken up by certainedible food items, thus food is often reported as a source of human exposure tocadmium (Anetor  2012). Cd is also present in tobacco smoke, further contributing tohuman exposure.The most dangerous characteristic of cadmium is that it accumulates throughout alifetime due to its long biological half-life (Hideaki et al. 2008). A peculiarity of  *Corresponding author. Email: teotia_anju29@rediffmail.com © 2013 Taylor & Francis  International Journal of Environmental Health Research , 2013http://dx.doi.org/10.1080/09603123.2013.835032    D  o  w  n   l  o  a   d  e   d   b  y   [   M  a  n  u   P  a  n   t   ]  a   t   2   0  :   2   3   1   4   O  c   t  o   b  e  r   2   0   1   3  cadmium is that it is a cumulative toxicant. Once absorbed, it is principally deposited inthe liver and kidney; hitherto considered critical target of cadmium toxicity, emergingevidence now suggest that this may be overtaken by genotoxicity (Anetor  2012).While the  󿬁 rst experimental toxicological studies are from 1919, the possibility that this metal could cause chronic effects in humans was recognized much later, with the 󿬁 rst reports of pulmonary, bone and renal lesions in industrial workers published in thelate 1930s  –  1940s (Bulmer et al. 1938; Nicaud et al. 1942; Friberg 1950). In the 1960s, cadmium was catapulted into the mainstream of metal toxicology research whencadmium was identi 󿬁 ed as the major etiological factor in  itai itai  disease, a conditionthat af  󿬂 icted Japanese women exposed to cadmium via their diet which containedcadmium contaminated rice and water (Nordberg 2009). After these early reports of severe intoxication, a number of epidemiological and experimental studies were carriedout worldwide in order to characterize the toxicity of Cd and to assess the exposurelevels from which this widespread pollutant could threaten human health.These studies have demonstrated that cadmium can cause a diversity of toxic effects.Soluble cadmium salts accumulate and result in toxicity to the kidney, liver, lungs, brain, testes, heart and central nervous system. Moreover, cadmium can cause osteopo-rosis, anaemia, non-hypertrophic emphysema, eosinophilia, anosmia and chronic rhinitis(Valko et al. 2005). In addition to the direct cytotoxic effects that could lead to apopto-tic or necrotic event, Cd has been implicated in the development of cancer and it has been classi 󿬁 ed as a type I carcinogen by the International Agency for Cancer Research(IARC 1993; Arroyo et al. 2012). The aim of the present article is to summarize current knowledge regarding the risks that this widespread pollutant may pose to human health. It includes the theories about the mech-anisms of the major toxic properties of cadmium ions, concentrating on biochemical andother mechanisms likely to be involved according to the laboratory and clinical literature. Cadmium toxicity Cd is an important occupational and environmental pollutant that causes damage tovarious organs (Friberg et al. 1986; Morselt  1991). It is extremely toxic and has toxic Table 1. Cadmium compounds and their respective sources.Cadmiumcompounds SourcesCadmium chloride Electroplating, photocopying, calico printing, dyeing, mirrors, analyticalchemistry, vacuum tubes, lubricants and as a chemical intermediate in production of cadmium-containing stabilizers and pigmentsCadmium sulphate Electroplating,  󿬂 uorescent screens, vacuum tubes, and analytical chemistry;as a chemical intermediate to produce pigments, stabilizers, and other cadmium compounds; as a fungicide or nematocide; and as an electrolyte inWeston cells (portable voltage standards)Cadmium nitrate Photographic emulsions, coloring glass and porcelain, in nuclear reactors,and to produce cadmium hydroxide for use in alkaline batteriesCadmium oxide NiCd batteries, as a catalyst, in electroplating, electrical contacts, resistant enamels, heat-resistant plastics, and manufacture of plastics (such as Te 󿬂 on)and nitrile rubbers, are used as a nematocide and ascaricide in swineCadmiumsulphidePigments for paints, glass, ceramics, plastics, textiles, paper and  󿬁 reworks.solar cells,  󿬂 uorescent screens, radiation detectors, smoke detectors,electron-beam-pumped lasers, thin- 󿬁 lm transistors and diodes, phosphors,and photomultipliers 2  A. Rani  et al.    D  o  w  n   l  o  a   d  e   d   b  y   [   M  a  n  u   P  a  n   t   ]  a   t   2   0  :   2   3   1   4   O  c   t  o   b  e  r   2   0   1   3   biological effects at concentrations smaller than almost any commonly found mineral.The mechanism responsible for cadmium-induced toxicity may be multifactorial. Cdexerts toxicity on the cells of various systems and tissues, such as the respiratory tract,the urinary, cardiovascular, gastrointestinal and nervous systems and the bones, by affect-ing their function either directly or indirectly. These toxic effects induce degeneration or even transmutation of the cells (Zarros et al. 2008).At the cellular level, cadmium (Cd) induces both the damaging and repair processesin which the cellular redox status plays a crucial role (Cuypers et al. 2010). The litera-ture provides clear evidence of the ability of Cd to provoke indirect oxidative damageon the DNA, leading to: (a) induction of cellular proliferation, (b) inhibition of theapoptotic mechanisms and (c) blocking of the DNA repair mechanisms (i.e. DNA-repair inhibition) (Zarros et al. 2008). Oxidative stress is assumed to be the principal molecular  basis underlying cytotoxicity caused by Cd. Oxidative stress Toxicities of transition metals, therefore, might be attributed to their oxidative tissuedamage property. Cellular studies indicate transition metals to be catalysts in oxidativereactions of biological macromolecules. Redox-active metals such as iron, copper andchromium undergo redox cycling, whereas redox-inactive metals such as lead, cadmium,mercury and others deplete cell ’ s major antioxidants, particularly thiol-containing antiox-idants and enzymes. Either redox-active or redox-inactive metals may cause an increasein production of reactive oxygen species (ROS) such as hydroxyl radical (HO − ), super-oxide radical (O 2. − ) and hydrogen peroxide (H 2 O 2 ). Enhanced generation of ROS canoverwhelm cells ’  intrinsic antioxidant defences, and result in a condition known asoxidative stress in cells that can be partially responsible for the toxic effects of heavymetals (Ercal et al. 2001).Cadmium, unlike other heavy metals, is unable to generate free radicals by itself;however, reports have indicated that the superoxide radical, hydroxyl radical and nitricoxide radicals could be generated indirectly (Galan et al. 2001). A study by Watanabeet al. (2003) showed generation of non-radical hydrogen peroxide, which by itself  became a signi 󿬁 cant source of free radicals via the Fenton reaction. Cadmium couldreplace the iron and copper from a number of cytoplasmic and membrane proteins likeferritin, which in turn would release and increase the concentration of unbound iron or copper ions. These free ions participate in causing oxidative stress via the Fenton reac-tions (Casalino et al. 1997; Waisberg et al. 2003) (Figure 1). The major enzymatic antioxidants are superoxide dismutase (SOD), which degradesO 2. − and catalase, and the glutathione (GSH) redox system, which inactivates H 2 O 2  andhydroperoxides. Three forms of SOD may be important: manganese SOD (which islocated in mitochondria), Cu  –  Zn SOD (which resides in the cytoplasm) and extracellular SOD (which lines blood vessels). Another important element is GSH (a water-soluble,low-molecular-weight tripeptide (L- γ -glutamyl-L-cysteinyl glycine)) present in highconcentrations in each cell. GSH is also present extracellularly and is particularlyabundant in lung epithelial lining  󿬂 uids (Cantin et al. 1987, 1989). In its antioxidant  capacity, GSH forms intermolecular disulphide non-radical end-product-oxidized gluta-thione (GSSG). GSH is also a cofactor for various enzymes that decrease oxidativestress (Heffner and Repine 1989; Bast et al. 1991; Halliwell 1996). In contrast, GSSG is either exported from the cell or converted to GSH by a reductase reaction that obtainselectrons from NADPH. GSH is abundant in the liver, and is thought to be the  󿬁 rst line  International Journal of Environmental Health Research  3    D  o  w  n   l  o  a   d  e   d   b  y   [   M  a  n  u   P  a  n   t   ]  a   t   2   0  :   2   3   1   4   O  c   t  o   b  e  r   2   0   1   3  of defence against Cd hepatotoxicity as Cd binds tightly to thiol groups, and depletionof hepatic GSH by diethyl maleate signi 󿬁 cantly enhances cadmium-induced hepatotoxic-ity (Dudley and Klaassen 1984). Depletion of hepatic GSH by diethyl maleate also dra-matically enhances Cd-generated POBN radical adduct signals in the bile suggestingthat disruption of the cellular GSH system is a key element for cadmium-induced oxida-tive stress in the liver (Liu et al. 2009).One of the most important effects of cadmium is depletion of selenium in the body.Selenium atoms combine with cadmium atoms and are escorted out of the body via the bile system. Therefore, there is less selenium to form GSH peroxidase, one of the body ’ s main antioxidants. This results in the formation of greater levels of ROS andhydrogen peroxide. Although, metallothionein (MT) has been shown to play a key rolein the detoxi 󿬁 cation of Cd, there is no effective therapy for Cd poisoning (Klaassen andLiu 1997). It has already been found that a single dose of cadmium chloride caused astatistically signi 󿬁 cant increase in lipid peroxidation and depletion of the reduced formof GSH in the liver of male mice and rats, accompanied by elevated activity of alanineaminotransferase (Caisová and Eybl 1986).The resulting oxidative stress leads to activation of transcription factors such as AP-1and nuclear factor-kappa B (NF- κ  B). The activation of these transcription factors by Cdhas been shown in intact animals and in cultured cells (Hart et al. 1999; Liu et al. 2002; Qu et al. 2005; Yang et al. 2007). However, under different experimental conditions, a decrease in NF- κ  B has also been reported (Xie and Shaikh 2006). The ROS sensitivenuclear factor E2-related factor 2 (Nrf2) is also activated by Cd-generated ROS (He et al.2008), in an attempt to combat oxidative stress in the cell.Cd is also known to activate the mitogen-activated protein kinases (MAPK) pathwaysvia ROS generation (Liu et al. 2002; Qu et al. 2006; Qu et al. 2007; Chen et al. 2008). This MAPK pathway is associated with signal transduction in response to oxidativestress. Cd, thus, also plays an essential role in eliminating oxidative damaged cells. Figure 1. General scheme of cadmium-induced oxidative stress. 4  A. Rani  et al.    D  o  w  n   l  o  a   d  e   d   b  y   [   M  a  n  u   P  a  n   t   ]  a   t   2   0  :   2   3   1   4   O  c   t  o   b  e  r   2   0   1   3
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