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Some of these heavy metals such as copper, cobalt, iron, nickel, magnesium, molybdenum, chromium, selenium, manganese and zinc have functional roles which are essential for various diverse physiological and biochemical activities in the body.
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Learn More »This chapter will highlight on the various sources of heavy metals and the processes that promote their exposure and bioaccumulation in the human body. More focus will be laid on the various mechanisms that lead to heavy metal toxicity with emphasis on macromolecule and cellular damages, carcinogenesis, neurotoxicity and the molecular basis for their noxious effects. The various toxic effects along with the signs and symptoms of some heavy metals in the human body will be discussed. These heavy metals are distributed in the environment through several natural processes such as volcanic eruptions, spring waters, erosion, and bacterial activity, and through anthropogenic activities which include fossil fuel combustion, industrial processes, agricultural activities as well as feeding [ 5 ]. These heavy metals do bioaccumulate in living organisms and the human body through various processes causing adverse effects. In the human body, these heavy metals are transported and compartmentalized into body cells and tissues binding to proteins, nucleic acids destroying these macromolecules and disrupting their cellular functions. As such, heavy metal toxicity can have several consequences in the human body. It can affect the central nervous function leading to mental disorder, damage the blood constituents and may damage the lungs, liver, kidneys and other vital organs promoting several disease conditions [ 6 ]. Also, long term accumulation of heavy metals in the body may result in slowing the progression of physical, muscular and neurological degenerative processes that mimic certain diseases such as Parkinson’s disease and Alzheimer’s disease [ 6 ]. More so, repeated long-term contact with some heavy metals or their compounds may even damage nucleic acids, cause mutation, mimic hormones thereby disrupting the endocrine and reproductive system and eventually lead to cancer [ 7 ]. Metals are natural constituents that exist in the ecosystem. They are substances with high electrical conductivity which voluntarily lose their electrons to form cations. Metals are found all over the earth including the atmosphere, earth crust, water bodies, and can also accumulate in biological organisms including plants and animals. Among the 35 natural existing metals, 23 possess high specific density above 5 g/cm 3 with atomic weight greater than 40.04 and are generally termed heavy metals [ 1 , 2 ]. Theses metals generally termed heavy metals include: antimony, tellurium, bismuth, tin, thallium, gold, arsenic, cerium, gallium, cadmium, chromium, cobalt, copper, iron, lead, mercury, manganese, nickel, platinum, silver, uranium, vanadium, and zinc [ 1 , 2 ]. This category of metals termed heavy metals have not only been known for their high density but most importantly for their adverse effects to the ecosystem and living organisms [ 3 ]. Some of these heavy metals such as cobalt, chromium, copper, magnesium, iron, molybdenum, manganese, selenium, nickel and zinc are essential nutrients that are required for various physiological and biochemical functions in the body and may result to deficiency diseases or syndromes if not in adequate amounts [ 4 ] but in large doses they may cause acute or chronic toxicities. This is a heavy metal which is used in industries to produce copper pipes, cables, wires, copper cookware, etc. It is also used to make copper intrauterine devices and birth control pills. Copper in the form of copper sulfate is added to drinking water and swimming pools [ 18 ]. Due to man’s anthropogenic and industrial activities, it can accumulate in the soil and up taken by plants. As such, copper is present in some nuts, avocado, wheat germ and bran etc. Chromium is a metal that is present in petroleum and coal, chromium steel, pigment oxidants, fertilizers, catalyst, oil well drilling and metal plating tanneries. Chromium is extensively used in industries such as wood preservation, electroplating, metallurgy, production of paints and pigments, chemical production, tanning, and pulp and paper production. These industries play a major role in chromium pollution with an adverse effect on biological and ecological species [ 16 ]. Following the anthropogenic activities by humans, disposal of sewage and use of fertilizers may lead to the release of chromium into the environment [ 16 ]. Therefore, these industrial and agricultural practices increase the environmental contamination of chromium. Environmental pollution by chromium has been mostly by the hexavalent chromium in recent years [ 17 ]. This metal is mostly used in industries for the production of paints, pigments alloys, coatings, batteries as well as plastics. Majority of cadmium, about three-fourths is used as electrode component in producing alkaline batteries. Cadmium is emitted through industrial processes and from cadmium smelters into sewage sludge, fertilizers, and groundwater which can remain in soils and sediments for several decades and taken up by plants. Therefore, significant human exposure to cadmium can be by the ingestion of contaminated foodstuffs especially cereals, grains, fruits and leafy vegetables as well as contaminated beverages [ 14 , 15 ]. Also, humans may get exposed to cadmium by inhalation through incineration of municipal waste. The metallic mercury is a shiny silver-white, odorless liquid metal which becomes colorless and odorless gas upon heating. Mercury is used in producing dental amalgams, thermometers and some batteries. Also, it can be found in some chemical, electrical-equipment, automotive, metal-processing, and building industries. Mercury can exist in a gaseous form thus it can be inhaled. Other forms of mercury contamination in humans may be through anthropogenic activities such as municipal wastewater discharges, agriculture, incineration, mining, and discharges of industrial wastewater [ 13 ]. Lead is a slightly bluish, bright silvery metal in a dry atmosphere. The main sources of lead exposure include drinking water, food, cigarette, industrial processes and domestic sources. The industrial sources of lead include gasoline, house paint, plumbing pipes, lead bullets, storage batteries, pewter pitchers, toys and faucets [ 11 ]. Lead is released into the atmosphere from industrial processes as well as from vehicle exhausts. Therefore, it may get into the soil and flow into water bodies which can be taken up by plants and hence human exposure of lead may also be through food or drinking water [ 12 ]. Arsenic is the 20th most abundant element on earth and the 33rd on the periodic table. The inorganic forms such as arsenite and arsenate compounds are lethal to humans and other organisms in the environment. Humans get in contact with arsenic through several means which include industrial sources such as smelting and microelectronic industries. Drinking water may be contaminated with arsenic which is present in wood preservatives, herbicides, pesticides, fungicides and paints [ 10 ]. Heavy metals are naturally present in our environment. They are present in the atmosphere, lithosphere, hydrosphere and biosphere [ 8 ]. Although these heavy metals are present in the ecosystem, their exposure to humans is through various anthropogenic activities of man. In the earth crust, these heavy metals are present in ores which are recovered during mining activities as minerals. In most ores heavy metals such as arsenic, iron, lead, zinc, gold, nickel, silver and cobalt exist as sulfides while others such as manganese, aluminum, selenium gold, and antimony exist as oxides. Certain heavy metals such as copper, iron and cobalt can exist both as sulfide and oxide ores. Some sulfides may contain two or more heavy metals together such as chalcopyrite, (CuFeS 2 ) which contains both copper and iron. During these mining activities, heavy metals are released from the ore and scattered in open in the environment; left in the soil, transported by air and water to other areas. Furthermore, when these heavy metals are used in the industries for various industrial purposes, some of these elements are released into the air during combustion or into the soil or water bodies as effluents. More so, the industrial products such as paints, cosmetics, pesticides, and herbicides also serve as sources of heavy metals. Heavy metals may be transported through erosion, run-off or acid rain to different locations on soils and water bodies. As reviewed from [ 9 ], the sources of specific heavy metals are described below. Most heavy metals are distributed in the body through blood to tissues [ 21 ]. Lead is carried by red blood cells to the liver and kidney and subsequently redistributed to the teeth, bone and hair mostly as phosphate salt [ 20 ]. Cadmium initially binds to blood cells and albumin, and subsequently binds to metallothionein in kidney and liver tissue. Following its distribution from blood to the lungs, manganese vapor diffuses across the lung membrane to the Central nervous system (CNS). Organic salts of manganese which are lipid soluble are distributed in the intestine for fecal elimination while inorganic manganese salts which are water soluble are distributed in plasma and kidney for renal elimination. Arsenic is distributed in blood and accumulates in heart, lung, liver, kidney, muscle and neural tissues and also in the skin, nails and hair. The regulatory limit for some selected heavy metals is shown in Table 1 . Humans may directly get in contact with heavy metals by consuming contaminated food stuffs, sea animals, and drinking of water, through inhalation of polluted air as dust fumes, or through occupational exposure at workplace [ 20 ]. The contamination chain of heavy metals almost usually follows this cyclic order: from industry, to the atmosphere, soil, water and foods then human [ 8 ]. These heavy metals can be taken up through several routes. Some heavy metals such as lead, cadmium, manganese, arsenic can enter the body through the gastrointestinal route; that is, through the mouth when eating food, fruits, vegetables or drinking water or other beverages. Others can enter the body by inhalation while others such as lead can be absorbed through the skin. Heavy metal may cause proteins to aggregate as arsenite-induced protein aggregation was observed and shown to be concentration-dependent. Also, the aggregates contained a wide variety of proteins enriched in functions related to metabolism, protein folding, protein synthesis and stabilization [ 79 ]. Saccharomyces cerevisiae (budding yeast) cells was shown to accumulate aggregated proteins after it was exposed to equi-toxic concentrations of cadmium, arsenite and chromium (Cr(VI)) and the effect of protein aggregation was influenced by heavy metals in this order: arsenic > cadmium > chromium [ 80 ]. The in vivo potency of these agents to trigger protein aggregation probably depends on the efficiency of their cellular uptake/export and on their distinct modes of biological action. Summarized in Figure 4 is the various mechanisms of heavy metal intoxication. Heavy metals may also inhibit protein folding. This was first observed when heavy metals such as cadmium, lead, mercury and arsenite were shown to effectively interfere with the refolding of chemically denatured proteins [ 78 ]. It was also observed that when protein misfolded in the presence of heavy metals, the misfolded protein could not be rescued in the presence of reduced glutathione or EDTA chelator. The order of heavy metal in terms of their efficacy in folding inhibition is mercury > cadmium > lead and correlates with the relative stability of their monodentate complexes with imidazole, thiol and carboxylate groups in proteins [ 79 ]. Also, heavy metal toxicity may be induced by the replacement of a metallo-enzyme by another metal ion of similar size. Cadmium displaces zinc and calcium ions from zinc finger proteins and metalloproteins [ 76 , 77 ]. For instance, cadmium can replace zinc in certain dehydrogenating enzymes, leading to cadmium toxicity. Such replacement can convert the enzyme structurally to an inactive form and completely alter its activity. These heavy metals in their ionic species such as Pb 2+ , Cd 2+ , Ag + Hg 2+ and As 3+ form very stable biotoxic compounds with proteins and enzymes and are difficult to be dissociated.
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Learn More »Heavy metal-bound proteins may be a substrate for certain enzymes. In such situations, the heavy metal-bound protein fits into an enzyme in a highly specific pattern to form an enzyme-substrate complex and thus cannot accommodate any other substrate until it is freed. As such, the product of the substrate is not formed as the enzyme is blocked and therefore, the heavy metal remains embedded in the tissue leading to dysfunctions, abnormalities and damages in the body. Inhibition of thiol transferases lead to increased oxidative stress and cell damage. For example, toxic arsenic present in fungicides, herbicides and insecticides can attack –SH groups in enzymes to inhibit their catalytic activities as shown in Figure 3 . When heavy metals are ingested through food or water into the body, they are acidified by the acid medium of the stomach. In this acidic medium, they are oxidized to their various oxidative states (Zn 2+ , Cd 2+ , Pb 2+ , As 2+ , As 3+ , Ag + , Hg 2+ , etc.) which can readily bind to biological molecules such as proteins and enzymes to form stable and strong bonds. The most common functional group that heavy metals bind is the thio groups (SH group of cysteine and SCH 3 group of methionine). Cadmium has been shown to inhibit human thiol transferases such as thioredoxin reductase, glutathione reductase, thioredoxin in vitro by binding to cysteine residues in their active sites [ 73 ]. The equations of these reactions are shown below (see [ 74 ] for review) ( Figure 2 ). Manganese is known to accumulate in the mitochondria of neurons, astrocytes and oligodendrocytes cells and disrupts ATP synthesis [ 65 ] by inhibiting the F1/F0 ATP synthase [ 65 ] or complex 1 (NADH dehydrogenase) of the mitochondrial respiration chain [ 66 ]. More so, it has recently been shown that manganese inhibits ATP synthesis at two sites in the brain mitochondria which are either the glutamate/aspartate exchanger or the complex II (succinate dehydrogenase) depending on the mitochondrial energy source [ 67 ]. The disruption of ATP synthesis by manganese leads to decreased intracellular ATP levels and generation of free radicals thereby increasing oxidative stress [ 68 ] which may contribute to manganese cellular toxicity [ 69 ]. Furthermore, manganese can oxidize dopamine (DA) to react with quinone species thereby disrupting the dopaminergic system (for review, see [ 70 ]). This has been shown in animal studies were manganese exposure has led to specific deficits in the dopaminergic system [ 71 ]. The DA reactive species are taken up by the dopamine transporter (DAT1) thus causing dopaminergic neurotoxicity [ 72 ]. Lead can decrease neurotransmission as long term exposure of rats to low levels of lead has shown reduction in the release of Ca 2+ -dependent glutamate and γ-aminobutyric acid (GABA) in the hippocampus [ 58 , 59 ]. This indicates dysfunction of presynaptic neuron signalization in the hippocampus as a result of lead exposure [ 60 ]. More so, lead exposure also impairs two postsynaptic currents; inhibitory post synaptic currents (IPSCs) and excitatory post synaptic currents (EPSCs) which are dependent on the release of presynaptic neurotransmitter such as glutamate and GABA. Thus, lead exposure leads to reductions in IPSCs and EPSCs indicating a deficit in glutamatergic and GABAergic neurotransmission systems. Also, lead has been shown to reduce the expression of key presynaptic proteins such as synaptobrevin (Syb) and synaptophysin (Syn) involved in vesicular neurotransmitter release [ 59 , 60 ]. Lead can disrupt neurotransmission by inhibiting the neuronal voltage-gated calcium (Ca 2+ ) channels (VGCCs) [ 61 ]. Thus, inhibition of presynaptic VGCCs may reduce the influx of Ca 2+ which is required for fast release of vesicular neurotransmitter thus interfering with neurotransmission. It is now suggested that inhibition of either NMDARs or VGCCs by lead would result in a significant decrease of Ca 2+ influx into the cell. Reduction of Ca 2+ entry into the cell will prevent neurotransmitter release and thus impair signalization leading to neurological disease states [ 62 , 63 ]. Lead can also reduce the expression of brain-derived neurotrophic factor (BDNF), a trans-synaptic signaling molecule that is released from both axons and dendrites which is involved in synaptic development and neurotransmitter release [ 64 ]. BDNF activity is also dependent on Ca 2+ and thus has been implicated in the development of neurological diseases. The NMDAR is known to enhance learning and memory mediated by the hippocampus [ 47 ] as this has been confirmed in animal studies in which animals exposed to lead during its developmental process exhibit similar learning deficits comparable to those with the absence or impaired NMDARs [ 48 , 49 ]. In the hippocampus, NMDAR is a neural receptor which consists of two or more subunits; an obligatory NR1 subunit and one or more subunits from the NR2 particularly NR2A, NR2B and NR3 families. Lead has been shown to be a potent, non-competitive antagonist of the NMDAR [ 50 , 51 , 52 , 53 ], preferentially with high affinity at a regulatory site on the NR2A subunit [ 54 ]. This has been further supported in electrophysiological studies in which recombinant receptors for the subunits have shown NR2A-NMDARs to be more potently inhibited by lead than NR2B-NMDARs [ 55 ]. More so, lead has been shown to decrease the content of NR2A in the hippocampus and also alter the expression of NR1 spliced variants [ 56 , 57 ] suggesting lead exposure disrupts the normal ontogeny of NMDAR. Nickel has an extensive range of carcinogenic mechanisms which include regulation of transcription factors, controlled expression of certain genes and generation of free radicals. Nickel has been shown to be implicated in regulating the expression of specific long non-coding RNAs, certain mRNAs and microRNAs. Nickel can promote methylation of promoter and induce the down regulation of maternally expressed gene 3 (MEG3) thereby upregulating hypoxia-inducible factor-1α, two proteins which are known to be implicated in carcinogenesis [ 44 ]. It has also been demonstrated that nickel can generate free radicals, which contributes to carcinogenic processes [ 45 ]. Little is known on the potential of mercury to act as a mutagen or carcinogen. However, the proposed mechanism of mercury-induced cancer is through the generation of free radicals inducing oxidative stress thereby damaging biomolecules. Mercury has been shown to induce malignant growth through the generation of free radicals as well as disruption of DNA molecular structure, the repair and maintenance system [ 43 ]. Arsenic-induced carcinogenic mechanisms include epigenetic alterations, damage to the dynamic DNA maintenance system and generation of ROS [ 36 , 37 ]. Alterations of histones, DNA methylation, and miRNA are the key epigenetic changes induced by arsenic which have shown to possess potentials to cause malignant growth [ 37 ]. In vitro studies have shown arsenic to alter the expression of p53 protein which also led to decreased expression of p21, one downstream target [ 38 ]. Arsenic compounds have been shown in an in vitro cell line study to promote genotoxicity in humans and mice leucocytes [ 39 ]. Also, a methylated form of arsenic was shown to inhibit DNA repair processes and also generate ROS in liver and spleen as metabolic products [ 40 ]. Arsenic can bind DNA-binding proteins and disrupt the DNA repair processes thereby increasing the risk of carcinogenesis. For example, the tumor suppressor gene-coded DNA was suppressed when arsenic was bound to methyl-transferase [ 41 ]. Also, cancers of the liver, skin, prostate and Kupffer cell were associated with Arsenic poisoning. Some heavy metals are known to have carcinogenic effect. Several signaling proteins or cellular regulatory proteins that participate in apoptosis, cell cycle regulation, DNA repair, DNA methylation, cell growth and differentiation are targets of heavy metals [ 34 ]. Thus, heavy metals may induce carcinogenic effect by targeting a number of these proteins. More so, the carcinogenic effects of certain heavy metals have been related to the activation of redox-sensitive transcription factors such as AP-1, NF-κB and p53 through the recycling of electrons by antioxidant network. These transcription factors control the expression of protective genes that induce apoptosis, arrest the proliferation of damaged cells, repair damaged DNA and power the immune system [ 22 ]. Metal signalization of transcription factor AP-1 and NF-κB has been observed in the mitogen-activated protein (MAP) kinase pathways where the nuclear transcription factor NF-κB, is involved in controlling inflammatory responses while AP-1 is involved in cell growth and differentiation [ 22 ]. The p53 protein is an important protein in cell division as it guards a cell-cycle checkpoint and control cell division [ 35 ]. Inactivation of p53 allows uncontrolled cell division and thus p53 gene disruption has been associated with most human cancers. Also, AP-1 and NF-κB family of transcription factors are involved in both cell proliferation and apoptosis, and also regulate p53. Heavy metals generated free radicals inside the cell selectively activates these transcription factors and thus, may suggest that cell proliferation or cell death may be related to the exposure to carcinogenic metals. There exist various mechanisms of heavy metal-induced carcinogenesis. Copper ions have been identified to participate in the formation of reactive oxygen species (ROS) as cupric (Cu 2+ ) and cuprous (Cu 1+ ) which can participate in oxidation and reduction reactions. The Cu 2+ in the presence of biological reductants such as glutathione (GSH) or ascorbic acid can be reduced to Cu + which is capable of catalyzing the decomposition of H 2 O 2 to form OH• via the Fenton reaction [ 26 ] as shown below. At the initiation stage, the radical (R • )/OH • attacks the lipid membrane to form a radial lipid. This radical lipid further propagates the formation of peroxyl lipid radical by reacting with dioxygen molecule or with a lipid. This reaction further promotes damage of the lipid molecule. At the termination stage, two radical lipid molecules and/or with a peroxyl lipid radical reacts to form a stable lipid molecule. The major aldehyde product of lipid peroxidation is malondialdehyde and it serves as a marker for lipid peroxidation. It is well documented that metal-induced generation of oxygen reactive species can attack polyunsaturated fatty acid such as phospholipids. The first of such observation was first presented by Bucher et al. [ 24 ] who showed that iron-generated OH • can oxidize lipid membranes through a process known as lipid peroxidation. Following his experimental observations, he proposed the following mechanism: Hydroxyl radical (OH • ) is the most common free radical generated by the oxidation of iron. OH • is capable of reacting with biological molecules such as proteins, lipids and DNA damaging them. When OH • reacts with guanine, a nitrogenous base of nucleic acids, it leads to the generation of 8-oxo-7,8-dihydro-20-deoxyguanosine (8-oxo-dG) and 2,6-diamino-5-formamido-4-hydroxypyrimidine (FAPy-G), in which the former is a good marker for oxidative damage [ 23 ].
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Learn More »Iron is a useful heavy metal in the human body as it is a constituent of certain biological molecules like the hemoglobin and involved in various physiological activities. However, in its free state, iron is one of the heavy metals generally known to generate hydroxyl radical (OH • ) as shown below by the Fenton reaction.
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