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International Journal of Bio-Technology and Research (IJBTR) ISSN 2249-6858 Vol. 3, Issue 1, Mar 2013, 17-36 TJPRC Pvt.

. Ltd.

A BRIEF REVIEW ON THE EFFECT OF CADMIUM TOXICITY: FROM CELLULAR TO ORGAN LEVEL
ANGSHUMAN SARKAR1, GEETHANJALI RAVINDRAN1 & VISHNUVARDHAN KRISHNAMURTHY2
1

Department of Biological Sciences, BITS Pilani, K K Birla Goa Campus, Zuarinagar, Goa 403726, India
2

Department of Cell and Developmental Biology, University of Illinois, IL, USA

ABSTRACT
Cadmium is a heavy metal classified as a group one carcinogen by IARC (1993) affecting multiple systems in humans and animals. Exposure to cadmium occurs primarily through ingestion of contaminated water, food and to a significant extent through inhalation and cigarette smoking. Cadmium poisoning came into prominence with the infamous itai-itai disease of the 1960s in Japan after ingestion of cadmium-contaminated rice. Cadmium has a long biological halflife (20 yrs) and primarily affects the kidneys, liver and intestine, while a prolonged exposure has proven to be carcinogenic to liver, kidney, lung, prostate, hematopoietic and other systems. In this regard, cadmium has been classified as a carcinogen. Studies at the cellular level under in vitro conditions have shown that cadmium exhibits multifarious actions which are yet to be comprehensively explained or united by any particular mechanism. Generally it forces the expression of the stress proteins and depending on factors such as amount of exposure, time of exposure, the cell line and presence of other chemical species, the outcome could be apoptosis, growth inhibition, proliferation or carcinogenicity in animal cells. The mechanisms leading to cadmium carcinogenesis are primarily those involving oxidative stress, inhibition of DNA repair mechanisms and augmenting or diminishing the tendency to apoptosis.

KEYWORDS: Cadmium, Toxicity, Cadmium Poisoning, Heavy Metal, Environment, Itai-Itai Disease, Stress INTRODUCTION CADMIUM PROPERTIES AND VARIOUS SOURCES
Cadmium (CAS registry number 7440-43-9) is a naturally occurring element of relatively poor abundance (64th amongst elements) in the earth's crust (0.1-0.5 ppm) with the symbol Cd and atomic number 48. While it occurs in air, water, soil as well as in tissues of plants and animals, it is not found in free State. Cadmium is present primarily in ores of zinc , copper or lead, the extraction and processing of which releases large quantities of cadmium into the atmosphere, hydrosphere and soil thereby contaminating the human environment. It is toxic, nonessential and classified as a human carcinogen by the North Carolina National Toxicology Program. [1] The physical and chemical Properties of cadmium namely corrosion resistance (particularly in alkaline and seawater environments), low melting temperature, rapid ion electrical exchange activity, high electrical and thermal conductivity (in both alloy and oxide forms) make it suitable for incorporation into batteries, alloys and for electroplating, welding, electrical, and nuclear fission applications [2]. Mainly, cadmium is used to produce colorants, stabilizers of plastics and electroplating protective coatings, solders and alloys, cadmium rods. It is also used for the production of alkaline nickel-cadmium batteries, fireworks and fluorescent paints [3].Moreover, as pigments cadmium compounds with stand high temperatures and disperse well in polymers producing strong colors with high opacity and good tinting strength. Cadmium compounds known as chalcogenides by virtue of their optical properties have found applications in plastics, paintings, enamels, inks, display devices, photovoltaic cells and more recently, quantum dots. The worldwide production of

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Cadmium in 2005 was estimated to be 20,000 metric tons. In table 1 the levels of cadmium in various sources have been given.

CADMIUM AS AN ENVIRONMENTAL POLLUTANT


Cadmium emissions arise from two major source categories, natural sources and man-made (anthropogenic sources). Emissions enter in to the three major compartments of the environment - air, water and soil. Emissions to air are considered faster than that to water which in turn are considered faster than that to soil. Natural Cadmium Emissions Cadmium is distributed throughout the environment from natural sources as well as processes such as the abrasion of rocks, erosion of soil, transportation of contaminated soil particles by wind and from singular events such as forest fires and volcanic eruptions. Average cadmium concentration in the earth's crust ranges from 0.1 to 0.5 ppm, although much higher levels may accumulate in sedimentary rocks. Marine phosphates and phosphorites have been reported to contain levels as high as 500 ppm. Major natural activities that emit cadmium include weathering and erosion of parent rocks and transportation to oceans [15,000 metric tonnes (mt) per annum] [5, 7], volcanic activity into the atmosphere (as high as 820 mt per year) [5,7 and 11] and to a lesser extent, forest fires (1 to 70 mt per year) [11]. Anthropogenic Cadmium Emissions Cadmium-Containing vs. Non-Cadmium Containing Products Anthropogenic activities contribute 310 times more Cadmium to the environment than natural activities [12]. Since Cadmium cannot be degraded, the risk of environmental exposure is constantly increasing because of accumulation via the food chain [13]. Man-made cadmium emissions can be from products intentionally incorporating cadmium (NickelCadmium Batteries ,Cadmium Pigmented Plastics, Ceramics, Glasses, Paints and Enamels, Cadmium Stabilized Polyvinylchloride (PVC) Products, Cadmium Coated Ferrous and Non-ferrous Products, Cadmium Alloys and Cadmium Electronic Compounds) or those in which cadmium is an impurity (Non-ferrous Metals and Alloys of Zinc, Lead and Copper, Iron and Steel, Fossil fuels like Coal, Oil, Gas, Peat and Wood, Cement and Phosphate fertilizers ). Moreover cadmium is a by-product of the extraction, smelting and refining of the nonferrous metals zinc, lead and copper and improper collection or disposal methods can lead to cadmium contamination of environment. Factors in Anthropogenic Emissions Analyses Several studies [5, 7 and 15] have identified three factors of primary importance in determining the levels of cadmium emissions. The first one, cadmium emission factors (amounts of cadmium emitted to the environment per unit of cadmium processed) tend to be lower in more technologically advanced regions of the world such as North America, Western Europe and Japan than in other regions [5, 14]. Second, data submitted by many countries are rather incomplete and lack information about cadmium release from unintended cadmium addition or use. Third, while cadmium levels in the environment has rapidly increased between the years 1800-1960 owing to industrialization and huge amount of fossil fuel combustion, the period post 1960 has seen drastic decrease in environmental cadmium levels due to improved emission control for fossil fuel combustion as well as improved technology for the production, use and disposal of cadmium and cadmium-containing products and tighter controls as well as stricter regulations [9]. Fourth, in many of its deliberate applications, cadmium or cadmium compounds are embedded in the products matrix, do not readily leach from the product, and are therefore not readily available. A notable example is products colored by cadmium sulfide pigments that are encased in plastics, glasses, ceramics or enamels, and which are therefore completely insoluble.

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Finally, many cadmium-containing products such as batteries, coatings and alloys are recyclable, (although at present recycling of only Ni-Cd batteries is commercially and economically viable). Success in the recycling largely depends on appropriate collection systems which seem to be limited to the developed world.

PERMISSIBLE LIMITS OF CADMIUM


Daily intake of cadmium from food by a person in different countries is at the level of 10-35 g per person.[108] The content of cadmium in food affects its concentration in the blood. Placenta protects the fetus from cadmium compounds. It was shown that in neonatal rats cadmium content is low and amounts to about 0.1 mg. The content of cadmium in adult body (at 50 years of age) is about 15-30 mg and increases with age [111]. This is due to the extremely long half-life of cadmium, which is estimated at 10-30 human years, an average of about 20 years [3]. A safe intake limit of 7 g cadmium/week/kg body weight or 25 g cadmium/kg body weight per month (mg/kg bw-mo) or 0.40.5 mg /week, and the maximum dose of 60-70 ug per day was set based on the critical renal cadmium concentration of between 100 and 200 g/g wet weight that corresponds to a urinary threshold limit of 510 g/g creatinine [18]. Provisional tolerable weekly intake (PTWI) for a chemical with no intended function is an estimate of the amount of the chemical that can be ingested weekly over a lifetime without appreciable health risk [18]. The PTWI value initially set for cadmium was 400500 g/person/week [18]. These levels were based on a critical renal concentration of 100200 g cadmium/g wet kidney cortex weight, attained after a cadmium intake of 140 260 g/day for > 50 years or 2,000 mg over a lifetime [18].The PTWI model incorporates an oral absorption rate of 5 % (retention about 0.5 to 1.0 g of cadmium per day from food) and a daily excretion rate of 0.005% of total body burden. A toxicokinetic model predicts, based on similar assumptions, that the renal cortical cadmium level of 50 g/g wet weight could be attained at the cadmium intake of 1 g/kg body weight/day over 50 years [19, 20]. Investigations around the world have shown that, for the general population, the average cadmium intake is low compared to the World Health Organizations (WHO) standard for tolerable cadmium intake and that cadmium intake levels have in fact been decreasing over the past 20 years. Average cadmium intakes in 1960 were about 15 g/kg bodyweight per month but by 2000 had decreased to about 5 g/kg body weight per month, well below the current WHO JECFA (Joint FAO/WHO Expert Committee on Food Additives) standard established in 2010 ( 25 g/kg body weight per month).

CADMIUM UPTAKE
Uptake through Food Because of its high rates of soil-to-plant transfer (via cation exchange in cell membranes and intracellular transport), the diet is the main source of environmental cadmium exposure (95%) in non-smokers in most parts of the world [21] although the uptake is inefficient (6%) [5]. Atmospheric deposition of airborne cadmium, mining activities and the application of cadmium-containing fertilizers and sewage sludge on farm land may lead to the contamination of soils and increased cadmium uptake by crops and vegetables grown for human consumption. High concentrations of cadmium are present in mollusks and crustaceans. As mentioned previously, certain foods contain high levels of cadmium. Based on estimation of cadmium intake, more than 80% of the food-cadmium comes from cereals, vegetables and potato. The average cadmium intake from food generally varies between 8 and 25 g per day of which approximately 0.5 to 1.0 g is actually retained in the body [22]. Factors influencing this mode of uptake are dose, exposure time, and chemical components of the diet, the body's nutritional status, age and gender.

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Uptake through Inhalation and Smoking Cadmium and its compounds enter the body primarily via respiratory tract(10-40%). People occupationally exposed to cadmium and cigarette smokers are at risk [23]. About 30- 64% of inhaled cadmium is absorbed by the body, with some variation as a function of chemical form, solubility and the particle size of the material inhaled [24]. Up to the l960s, elevation of cadmium in air than the permissible air exposure levels was measured in some workplaces, sometimes as high as 1 mg/m. Since that time, workplace exposures and standards have decreased markedly so that most occupational exposure standards today are in the range from 2 to 50g/m. The result has been that occupational exposures today are generally below 5g/m, and most industrial workers are exposed at levels which are considered to be safe. In areas with contaminated soils, house dust is potentially an important route of exposure to cadmium, even after the closure of the cadmium emitting source. An important source of cadmium in the human body is cigarette smoke. After the burning of a cigarette containing an average of 1-2g of cadmium, 0.1-0.2g of this element reaches the smoker's lungs ( about 1 to 3g of cadmium per day for a person smoking 20 cigarettes per day).During the many years of smoking (e.g. 20 years) nearly 15 mg of cadmium is introduced into the smokers body [3]. Reports say that the milk of mothers who smoke may contain twice more cadmium than milk of nonsmoking mothers and blood level of Cd in smokers is signicantly higher than that of non-smokers. Van Assche et al. [16] has developed a model for cadmium exposure for human beings and allocated this exposure to the various sources in particular, in the Environmental Resources Limiteds report on the sources of human and environmental contamination in Europe [17] and the updated data on cadmium emissions contained in the OECD Monograph on Cadmium [7].

TRANSPORT AND STORAGE OF CADMIUM


With a single exposure to the organism, cadmium accumulates primarily in the liver. Low molecular weight protein called Metallothionenins (MT) in the liver form complex with Cadmium (CdMT complexes). Released from the liver into the blood CdMT complexes end up in various tissues and organs of the human body. Prolonged exposure to low doses of cadmium results in their increased accumulation in the kidneys, especially in the cortical part [107,109]. Distribution of cadmium in the body depends on the chemical form of this element. Increased accumulation of Cd2+ ions in the liver, kidneys or bones occurs after exposure to cadmium in the form of inorganic salts (eg CdCl2) than the cadmium present in conjunction with metallothionein (CdMT). CdCl2 accumulates mainly in the liver, whereas CdMT in the kidney. The organs that store Cadmium include the liver, kidney, testis, spleen, heart, lungs, thymus, salivary glands, epididymis, and prostate; however, approximately 50% of the Camiumd found in the body is stored in liver and kidney due to their high MT concentration [25, 108and 110]. Cadmium can also accumulate in the pancreas, lungs, central nervous system and testes in men. Cadmium particles are transported along primary olfactory neurons to their terminations in the olfactory bulb. Some other metals, such as manganese, do migrate further into the brain, unlike cadmium which accumulates in the olfactory bulb [26]. Another site of cadmium accumulation after inhalation is lungs, as observed with smokers for instance. Although the lung epithelium is an efficient barrier for toxic molecules and heavy metals, cadmium can pass through alveolar cells and get into the blood [27]. The ingestion of cadmium-containing food and water is the other major source of animal exposure providing ~30 g per day for an adult [28]. The acidic environment of the digestive tract favors cadmium transport by the broad specificity proton-metal cotransporter DMT1, (also DCT1, Nramp2, or SLC11A2 and the conveyor MTP1 metal ions (metal transporter protein 1) [28] at the apical membrane of enterocytes. DMT1 repression in a human enterocyte model

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decreases cadmium transport whereas its over expression strongly increases cadmium uptake [27]. Cadmium uptake from the gastrointestinal tract is strongly influenced by the content of protein, zinc and copper compounds ,calcium and iron in the diet. Their low content in the diet increases the absorption of cadmium from the gastrointestinal tract and its accumulation in the body. Increased amount of zinc in the diet reduces the intensity of the absorption of cadmium from the gastrointestinal tract. This follows from the fact that the absorption of cadmium is done with the participation of transport systems of the ions of zinc, copper, iron and calcium and comes to the competition between the metals of the conveyor [29]. The absorption of cadmium is not only related to the transport of iron. It can also be done by simple diffusion or through a system of membrane transport proteins (hZTL1 and ZNT1) responsible for the transport of zinc and calcium ions [30]. Cadmium can also be absorbed from the gastrointestinal tract in combination with thiol groups of cysteine-SH and glutathione (GSH) as the Cd-cysteine, Cd-GSH [31]. Absorbed cadmium is transported to the liver.

CADMIUM EXCRETION
Cadmium is excreted primarily in urine. Its quantity in the urine may be an indicator of the amount of the metal in the body. Small amounts of cadmium usually conjugated with glutathione, cysteine or metallothionein are excreted in the feces [31]. The daily excretion of cadmium from the body (mainly by the kidneys) does not exceed 0.01% of the amount of this element consumed in the diet [106].

CADMIUM TOXICITY IN HUMANS


Toxicity at Organ System Level Cadmium poses a great health risk to humans even at very low concentrations in the body and because the body has limited capacity to respond to cadmium exposure, as the metal cannot undergo metabolic degradation to less toxic species and is poorly excreted [32]. The target organs for cadmium toxicity in animals include the liver, kidney, lungs, testes, prostate, heart, skeletal system, nervous system and immune system. However, prolonged human exposure to Cd results in its accumulation in the body and leading to diseases mainly affecting lungs and kidneys [23]. Symptoms of acute cadmium poisoning usually appear after 24 hours are: shortness of breath, general weakness, fever. It can also cause pulmonary edema, pneumonia, and in severe cases, respiratory failure and death [33]. Women have higher cadmium body burden than men, reected as higher concentrations of cadmium in blood, urine and kidney cortex [34, 86]. The main reason for the higher body burden in women is increased intestinal absorption of dietary cadmium. [22]. Blood cadmium is considered the most valid marker of recent exposure and is usually assessed in whole blood. Kidney and Bone Long-term exposure to high-dose cadmium causes Itai-itai disease. This disease affects mainly women and is characterized by severely impaired tubular and glomerular function and generalized osteomalacia and osteoporosis that result in multiple bone fractures [35]. A long-term exposure to low-dose cadmium has been linked to tubular impairment with a loss of reabsorptive capacity for nutrients, vitamins, and minerals and nephropathy and proteinuria [37]. These non absorbed molecules include [86] zinc or copper bound to the metal binding protein metallothionein (MT), glucose, amino acids, phosphate, calcium, low-molecular weight (LMW) proteins, such as 2-microglobulin(2-M) / 1microglobulin(1-M), also called proteinHC, retinol- binding protein (RBP) and also uric acid, [36] bearing similarities with Fanconis syndrome, a genetic disorder of renal tubular transport. Urinary markers for cadmium effects are cadmium itself, low-molecular-weight proteins (2-M, 1-M), and the enzymes of renal tubular origin, such as the lysosomal

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enzyme N- acetyl glucosaminidase (NAG). In general, the urinary cadmium level reflects the body burden over long-term exposure before the development of kidney damage, and blood cadmium is considered an indicator of recent exposure [36]. Because cadmium in the cells interferes with the metabolism of calcium, magnesium, iron, zinc and copper, it leads to demineralization, osteomalacia and osteoporosis and disorders of the bones of the body, in which it is necessary to replace these ions. Competitive displacement of calcium ions by cadmium from the bones weakens their structure, which is very often the cause of fractures, especially in children and women during menopause. Cadmium inhibits the activity of 1-hydroxycholecalciferol hydroxylase-the enzyme responsible for metabolism in the kidney converting 25(OH)D3 to 1,25(OH)2D3, which is the active form of vitamin D3. Its presence in the intestine is essential for the absorption of calcium ions [105]. Lung Inhalation causes respiratory stress and injures the respiratory tract. Emphysema, anosmia and chronic rhinitis have been linked to high cadmium concentrations in polluted air. Lampe et al., [38] examined the potential effects of exposure to cadmium on lung function using a sample group of 96 men who underwent one to three lung function tests between 1994 and 2002. They found a reduction in forced expiratory volume in 1 sec (a reflection of lung function) associated with increased urinary cadmium among those who smoked. Cadmium poisoning by inhalation leads to respiratory distress syndrome. Periodontal Tissues In a study with 11,412 participants in which 15.4% having periodontal disease a 3-fold increase in urinary cadmium (0.18 versus 0.63 g/g creatinine) has been reported to be associated with a 54% higher prevalence odds ratio (OR) for periodontal disease [39]. Mammary Gland Breast milk samples of Austrian subjects contained, on average, a cadmium content of 0.086 g/L and that breast milk cadmium content was lower among nonsmokers who took vitamins and mineral supplements (p < 0.05) [40]. Blood Vessels and the Heart A set of studies has found evidence linking an increased risk of PAD (peripheral artery disease) with low-dose cadmium exposure [41]. This element also adversely affects the cardiovascular system. Experimental studies have shown particular sensitivity of the vasculature of various organs, especially endothelial cells to the toxic effects of Cadmium. Cadmium induces impaired function and structure of endothelial damage and vascular smooth muscle cells, which favors the formation of atherosclerotic plaque. This is confirmed by epidemiological and clinical studies [42]. Smokers had an increased amount of cadmium in the blood and the occurrence of atherosclerosis, notably peripheral vascular disease is more in them compared to non- smokers [43]. GI Tract In the stomach, cadmium reacts with hydrochloric acid and Cadmium Chloride forms, which can induce acute inflammation of the gastrointestinal tract [44]. Reproductive System Cadmium adversely affects the reproductive functions. Exposure to cadmium toxicity primarily impairs testicular function. Mechanisms of toxic effects of cadmium in the testis include damage to the vascular endothelium,

A Brief Review on the Effect of Cadmium Toxicity :From Cellular to Organ Level

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Leydig and Sertoli cells, intercellular connections, the induction of oxidative stress, impaired antioxidant defense mechanisms and the severity of the inflammatory response, which results in their morphological and functional changes like Inhibition of testosterone synthesis and spermatogenesis impairment. Cadmium also interferes with prostate function, which alters its hormonal activity, secretion and impairs fertility in men [45]. Immune System Exposure of cadmium to the body, especially chronic exposure, leads to mal-functioning of the immune system. Because the target cells of cadmium are T cells [cytotoxic K (killer) cells], macrophages, B cells and NK (natural killer ) cells. It shows that the direct immunotoxicity by cadmium is a modification of the immune responses of both- cell mediated and humoral immunity [46, 47]. There are also reports suggesting anemia and eosinophilia have been associated with cadmium intoxication [104]. Cadmium as a Multi-Tissue Carcinogen International Agency for Research on Cancer (IARC, 1993) classied cadmium as a human carcinogen (group I) on the basis of classified level B.1 (evidence level for inhalation route according to EPA Weight-of-Evidence ) [10 and 92]. Multiple studies [86] have linked occupational exposure to cadmium with pulmonary cancer [48], as well as prostate [23, 33 & 49], renal [50], liver [23, 55], hematopoietic system [23, 55], mammary gland [51], endometrium [53], urinary bladder [52], pancreatic [54], and stomach cancers [23, 55].

MECHANISM OF CADMIUM TOXICITY


Interference with Essential Metals In all likelihood, cadmium being a divalent cation is accumulated by transport mechanisms developed for essential metals. From physical and chemical properties, those metals are most likely to be zinc, iron, magnesium, manganese, calcium and selenium. Cadmium may interact with these elements and cause their secondary deficit thereby disrupting metabolism, resulting in the final morphological and functional changes in many organs. Interaction apoptosis induced by cadmium ions [58]. Disruption of Signaling and Biomolecules Toxicity could result from Cadmium (Cd2+) interacting with cellular components even without entering the cell, but by interaction with receptors on their surface [59]. Cadmium forms covalent and ionic bonds with atoms of sulfur, oxygen and hydrogen present in the sulfhydryl groups, disulfide, carboxyl, imidazole or multiple amino compounds present in the cells, causing significant disruption of their homeostasis [60]. There are many data indicating the adverse effect of cadmium on cellular signaling pathways. This interferes with the reception and processing in the cells where the external signals reach and prevent their proper functioning. Cadmium may interfere with cell signaling at every stage of signal transduction and can act on receptors, second messengers, transcription factors [103] . The main target organelle of cadmium is the mitochondria [61]. Cadmium enters the mitochondria through calcium channels and induces conformational changes in proteins located in the membrane by binding to thiol groups and consequently interfere with oxidative phosphorylation and alter its membrane permeability leading to reduction in membrane potential, decrease in cellular ATP levels, disturbances in homeostasis of calcium, sodium, potassium and ultimately leakage of cytochromes, Fe (II) ions leading to increased ROS and a variety of effects. Consequences include increased production of reactive oxygen species and changes in the expression of different genes, which trigger cell cycle arrest, differentiation, immortalization, or apoptosis. Ubiquitin binding to protein substrates is often signaled by post-translational modifications, of cadmium with iron, copper and zinc are fairly well understood and described [56, 57]. Zinc also prevents cell

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such as glycosylation or phosphorylation [100, 101]. These processes may be activated by cadmium. For instance, incubation of human cell lines with cadmium decreases the levels of proteins like eIF4AE, a eukaryotic translation initiation factor. This occurs neither by decreased transcription nor by mRNA half-life shortening, but by decreased protein stability [62]. Increased protein stability has also been reported [102]. According to [63] the mechanism of carcinogenic action of cadmium may also involve disruption of intercellular signaling and cytoskeletal damage which leads to changes in cell adhesion, which plays a major role in regulating processes such as growth, differentiation and cell migration. This involves the ability of cadmium to modify the E-cadherin and -catenin responsible for the integrity of tissues. The exchange of calcium in E cadherin with cadmium leads to changes in the conformation of these proteins, which destroys the intercellular connections, and comes to the activation of -catenin and to uncontrolled proliferation, apoptosis and disrupts or promotes the development of cancer. Impaired signaling by cadmium can also be done at transcriptional and translational level. Action of cadmium leads to increased concentration of calcium ions, which by activation of protein CREB (cAMP response element binding protein) interacting with specific sites in the promoter region may directly induce gene expression [64]. Cadmium can activate protein kinases responsible for phosphorylation of transcription factors such as AP-1, NF-B, MTF-1 and other proteins. Results show that activation of MTF-1 by the metal ions is a result of its phosphorylation and increased translocation of MTF-1 from the cytosol to the nucleus, the consequence of which was increased activation of genes and their expression [98, 99]. According to Ravindran et., al (unpublished data) cadmium alters morphology of human lung cancer cells (at concentration level of 25M to 75M) by modulating the expression of small GTPase genes- Rho, Rac and CDC 42. Changes in Methylation It is known that metals and metalloids cause cancer primarily by direct interaction with DNA. Since cadmium is poorly mutagenic it may well act as an epigenetic or indirect genotoxic carcinogen [55]. Yet another impact of cadmium on the activation and gene expression may be inhibition of DNA methylation [65]. In the case of hypomethylation, overexpression and excessive synthesis of protein products occur which are responsible for increased cell proliferation, which may result in the development of malignancies . Three independent studies have reported cadmiuminduced changes in global and gene specific DNA methylation levels [66,67& 68]. The relation between the alteration of DNA methyltransferase activity and cell proliferation induced by Cd remain to be studied. Presently, no studies have reported an effect of cadmium on histone tail posttranslational modifications. Based on the promoter specific effects on DNA methylation and histone methylation status observed with both nickel and chromium treatment it is likely that cadmium regulates the expression of genes important for carcinogenesis by writing and erasing epigenetic marks on the promoters of these genes [85].

CADMIUM AND CARCINOGENESIS


The major mechanisms involved in Cadmium carcinogenesis can be broadly categorized into four groups, aberrant gene expression, inhibition of DNA damage repair, inhibition of apoptosis, and induction of oxidative stress, with signicant overlap among the groups [68]. In addition, the ability of Cadmium to cause aberrant DNA methylation, endocrine disruption and cell proliferation may assume minor importance with respect to its carcinogenic potential. Aberrant Gene Expression This takes place in following five categories: 1. immediate early response genes, 2. stress response genes, 3. transcription factors, 4. translation factors.

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Immediate Early Response Genes (IEGs) Cadmium is found to induce over-expression of one or more IEGs (c -fos, c-jun and c-myc) in a variety of cell lines, including rat L6 myoblasts [116], rat kidney NRK-4 9 cells [113], rat and human mesangial cells [115], human prostate epithelial cells[112] and in mouse embryonic broblasts[114].Cadmium-induced overexpression of the IEGs can be transitional, lasting for a few hours [69] or sustained, such as in the case of cells that are transformed by exposure to Cadmium [70]. C-fos and c-Jun, two of the Cadmium-responsive IEGs, constitute the AP-1 transcription element that is present in the promoter regions of several genes involved in cell growth and division. The increase in ROS in the cell under the influence of cadmium alters the expression of many genes such as transcription factor AP-1 [70]. The Cadmium-induced overexpression of c-fos and c-jun has been observed in cells transformed upon exposure to Cadmium and has been suggested as a possible mechanism responsible for Cadmium carcinogenesis [70] Stress-Response Genes These are involved in the synthesis of MT, those encoding heat shock proteins, those responsible for glutathione (GSH - the most important antioxidant molecule present in cells) synthesis and homeostasis, and those involved in oxidative stress response. Mouse lungs contain signicantly higher amounts of MT compared to rat lungs, and the induction of lung cancer observed in mice exposed to Cadmium is signicantly lower compared to that of rats [23]. The enhanced testicular toxicity seen in rats in response to their exposure to Cadmium was found to be associated with a lack of induction of MT genes in the Sertoli and spermatogenic cells, further supporting a protective role for MT in Cadmiuminduced testicular toxicity in rats [97]. GSH and its enzymes, such as GSH peroxidase and GSH reductase play a major role in the detoxication of Cadmium. Induction of -glutamyl cysteine synthetase facilitating enhanced GSH synthesis should be considered as the key mechanism underlying the GSH-mediated protection from Cadmium carcinogenesis [92].Exposure of cells and animals to Cadmium is known to induce several genes encoding heat shock proteins [71]. It has been hypothesized that protein denaturation or any other type of protein damage caused by Cadmium serves as the stimulus for induction of the genes encoding heat shock proteins [72]. Transcription Factors Some of the genes that are induced by the exposure of cells to Cadmium encode transcription factors which can result in transcriptional de-regulation of their target genes. The transcription factors that are activated by the exposure of cells to Cadmium are the metal regulatory transcription factor 1 (MTF1), upstream stimulator factor (USF), nuclear factor B (NFB) and NFE2-relatedfactor 2(NRF2) [93,94, 95 and 96]. Mechanisms of Cadmium-induced differential gene expression include the binding of the transcription factor MTF1 to the metal response element (MRE) sequence present in the promoter regions of these genes [77]. However, a signicant suppression of the DNA binding activities of the HIF1 and SP1 transcription factors has also observed in cells treated with Cadmium [73, 74]. Translation Factors Studies from recent years indicate that cadmium may interfere with the process of translation. This may be by over expressing the translation factors like initiation factors (eg TIF3) or elongation factors (eg TEF-1). Overexpression of translation initiation factor 3 and translation elongation factor 1 delta have been observed in cells which had undergone tumor transformation by cadmium treatment [75]. Transfection of cells with cDNAs encoding these Cadmium-responsive translation factors resulted in cell transformation and tumorigenesis further supporting the oncogenic potential of the Cadmium-responsive translation factors [76].

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CADMIUM AND APOPTOSIS


Cadmium interferes with the structure and function of several molecules with marked endpoints such as cell death and (uncontrolled) cell proliferation. Milder forms of Cadmium stress, however, can also result in the activation of cellular repair mechanisms. In general, Cadmium induces both damaging as well as protective signaling pathways, but the exact underlying mechanisms remain to be resolved. Several studies focus on apoptosis as an important process mediating Cadmium-toxicity in different organs but non-apoptotic cell death is also apparent [78]. When applied in low to moderate concentrations under in vivo and in vitro conditions, Cadmium mainly causes apoptosis [79]. The exact mechanisms of execution (extrinsic, intrinsic or caspase-independent pathways), however, remains controversial as several investigations using different cell types and different doses yield diverse outcomes. Achanzar et al.,[80] demonstrated that, cadmium exposure in cell lines results in malignant transformation by the activation of genes, such as c-jun and c-myc that are involved in cell proliferation as well as by the down regulation of p53 tumor suppressor gene and inhibition of apoptosis. The inhibitory effect of Cadmium on apoptosis induced either by it or by other carcinogenic chemicals may represent a major non-genotoxic mechanism for its role as a carcinogen and/or cocarcinogen which allows a greater portion of genetically damaged cells to survive or give selective growth advantages to pre-neoplastic cells that result in malignant transformation and carcinogenesis. There is considerable evidence to demonstrate the involvement of multiple mechanisms underlying Cadmium-induced necrosis and apoptosis. Induction of oxidative stress is another factor modulating the cellular level of Ca2+ and the activities of caspases and mitogen activated protein kinases (MAPKs) in the cells. Inhibition of Cadmium-induced apoptosis by the antioxidants, N-acetyl cysteine (NAC), glutathione, and catalase, further support the role of oxidative stress in Cadmium-induced apoptosis [81]. Suppression of the activity of the transcription factor NFB has been suggested as a mechanism responsible for the Cadmium-induced apoptosis .The inhibitory effect of Cadmium on chromium-induced apoptosis in CHO K1-BH4 cells is mediated through the inhibition of caspase 3 activities, a central mediator of apoptosis [82].

CADMIUM AND OXIDATIVE STRESS


At the cellular level, Cadmium induces oxidative stress in many organisms [83], which might result in physiological damage to different organs like kidneys, liver, lung, pancreas, testes, placenta, and bone [33].Cadmium is a bivalent cation and is unable to generate free radicals directly, nevertheless the production of reactive oxygen species (ROS) after Cadmium exposure has been reported in multiple studies. The effects of Cadmium-induced oxidative stress in the cells and tissues of animals and plants are outlined in reviews [64, 83]. Cadmium is unable to catalyze redox reactions in biological systems under physiological conditions. It has been shown, however, that Cadmium increases the concentration of free redox-active metals like Fe (II), Cu (II) possibly by their replacement in various proteins, changes in mitochondrial membrane potential and inhibiting the flow of electrons from reduced ubiquinone to cytochrome c and these free redox-active metals directly enhance the production of OH (hydroxyl) radicals through the Fenton reaction. Reduction of the oxidized metal ion can be achieved by the HaberWeiss reaction with superoxide radicals (O2 -) as a substrate, but also other reducing agents, such as ascorbate can catalyze this reaction. The cellular responses against oxidative stress balance between cell death and cell proliferation, and signaling molecules such as p38-MAPK (Mitogen-Activated Protein Kinase) and JNK (Jun N-terminal Kinase) are involved in both stress-induced processes [84]. The exact role of ROS in the activation of signal transduction pathways involved in defense mechanisms during Cadmium stress, still needs to be claried. The oxidative stress that arises in cells exposed to cadmium weakens their antioxidant defense mechanisms, results in reduction of glutathione - SH-related proteins and

A Brief Review on the Effect of Cadmium Toxicity :From Cellular to Organ Level

27

changes antioxidant enzyme activity, activates proto-oncogenes, which leads to excessive production of protein products that stimulate cell proliferation [87]. Low efficiency of antioxidant mechanisms in cells exposed to cadmium may result from the interaction of cadmium with zinc, copper, iron and selenium resulting in a decrease in activity of antioxidant enzymes: superoxide dismutase, catalase, glutathione peroxidase. Regardless of the mechanism of induction of oxidative stress in cells by cadmium, increase in ROS occurs, which leads to the damage and changes in their structure and metabolism [90, 91]. Their excess induces mitochondrial membrane lipid peroxidation, which can cause damage to these organelles. ROS reacting with polyunsaturated fatty acids of cell membranes initiate lipid peroxidation process that results in modification of proteins, changes in membrane gradient, and this causes the loss of their integrity and irreversible damage. In light of the current state of knowledge of the mechanism of cadmium toxicity is the induction of oxidative stress in cells, the consequence of which is primarily peroxidation damage to cell membranes [88, 89] [Refer fig. 2].

CONCLUSIONS
In this review have discussed various intracellular effect of cadmium in general [Refer Fig 3]. As of now, therapeutically effective chelating agents to enhance excretion of cadmium are lacking, and this factor makes prevention of cadmium accumulation pivotal. The persistence of cadmium in the environment requires a long-term approach to minimize human exposure through environmental management and maintenance of lower cadmium levels wherever possible [87]. Varied effects of Cadmium under different conditions in different cell lines have rendered the possibility of a specific mechanism evasive. Such being the case, it is necessary to profile the effects comprehensively and identify the common themes in cadmium toxicity for further progress to be made in this regard.

ACKNOWLEDGEMENTS
Authors thanks Ms. Manashree Malpe for her help in preparation of this manuscript. Financial support from BITS Seed Grant Fund and BRNS project (No. 2011/37B/25/BRNS) to AS is duly acknowledged. GR is supported by CSIR JRF from Govt. of India.

Figure 1

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Angshuman Sarkar, Geethanjali Ravindran & Vishnuvardhan Krishnamurthy

Figure 2

Figure 3 Figure 3 Legend: Schematic Representation of intracellular effects of cadmium: It is believed that cadmium mainly enters an animal cell through three transmembrane transporters, DMT1 or Divalent Metal ion Transporter 1,Voltage Gated Ca2+ Channels, Zip8. Inside the cell, cadmium (1) binds to metalloproteins displacing Fe Mn Cu Zn etc, either leading to misfolding of the protein or eventual production of Reactive oxygen Species ROS or Reactive Nitrogen Species RNS leading to oxidative damage followed by cell death,(2)binds to metallothionein displacing Zn2+ which in turn binds to MTF1 transcription factor ,which translocates to nucleus to initiate transcription of its target genes,(3)binds to specific receptors on ER membrane leading to release of calcium, which in turn will either activate caspases leading to apoptosis or activate certain kinases and phospahtases resulting in transcription of cell cycle genes leading to cell proliferation or binding of ca2+ will lead to proteasomal degradation of these proteins and (4)initiate apoptosis by mitochondrial pathway.

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Table 1 Level of Cadmium in the Environment 1.1 Ambient air 0.003-0.6 g/m3[3] 1.2 Occupational environment 2-50 g/m3[6] 1.3Tobacco smoke 0.5-2 g/cigarette [5,6] 2.1Ocean 5-110ng/L[6,7] 2.2Surface water(Rain, River etc) 10-4000ng/L[5,6and7] 2.3Ground water Less than 0.1ppm[7] 3.1 (From fertilizers) 10-100 g/kg [8] 4.1. Vegetables 4.2 Meat and fish 30-150ppb[10] 5-40ppb[10]

1. Air

2.Water

3. Soil 4.Food Stuffs

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