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Biochemical and Molecular Bases of Lead induced toxicity in mammalian systems and possible mitigations Nitika Singh, Abhishek Kumar, Vivek kumar Gupta, and Bechan Sharma Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/acs.chemrestox.8b00193 • Publication Date (Web): 04 Sep 2018 Downloaded from http://pubs.acs.org on September 5, 2018
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Chemical Research in Toxicology
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Biochemical and Molecular Bases of Lead induced toxicity in mammalian systems and
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possible mitigations
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Nitika Singh, Abhishek Kumar, Vivek Kumar Gupta and Bechan Sharma*
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Department of Biochemistry, Faculty of Science, University of Allahabad, Allahabad-211002,
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India
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*
corresponding author: Email:
[email protected]; Contact: +91-9415715639
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Table of Contents (TOC) graphic
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Abstract
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The effects of lead exposure on to the mammals are reported to be devastating. Lead is present in
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all the abiotic environmental components such as brass, dust, plumbing fixtures, soil, water, and
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lead mixed imported products. Its continuous use for several industrial and domestic purposes
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has caused rise in its levels thereby posing serious threats to human health. The mechanisms
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involved in lead-induced toxicity primarily include free radical mediated generation of oxidative
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stress which directly imbalance the prooxidants and the antioxidants in body. The toxicity of lead
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involves damage primarily to major biomolecules (lipid, protein and nucleic acids) and liver
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(hepatotoxicity),
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(genotoxicity), present in animals and humans. The activation of c-Jun NH2-terminal kinase
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(JNK), Phosphoinositide (PI) 3-kinase or Akt and p38 mitogen activated protein kinase (MAPK)
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signaling pathways are important for lead cytotoxicity. Lead increased apoptosis through
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signaling cascade and associated factors and significantly impairs cell differentiation and
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maturation. In addition, lead has the great impact on metabolic pathways such as heme synthesis
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thereby leading the onset of anemia in lead exposed people. This review encompasses an updated
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account of varied aspects of lead induced oxidative stress and their biomolecular consequences
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such as perturbations in physiological processes, apoptosis, carcinogenesis, hormonal imbalance
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and loss of vision and reduced fertility and their possible remediation through synthetic
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(chelators) and natural compounds (plant-based principles). This communication primarily
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concerns with the biomedical implications of lead induced generation of free radical and their
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toxicity management in mammalian system.
nervous
system
(neurotoxicity),
kidney
(nephrotoxicity)
and
DNA
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Keywords: Lead, Oxidative stress, Toxicity, Signaling pathways, Apoptosis, Carcinogenesis and
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Remediation
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1. INTRODUCTION
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Lead is the one of the crucial and natural toxic metal among all the heavy metals1 of the earth’s
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crust. Lead originated from Latin word plumbum, atomic number 82, is a widely distributed
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toxin. The use of lead can be retraced from the ancient times2. Lead is detectable in all phases in
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living systems as well as inert environment. The enhanced anthropogenic activities and vehicular
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emissions are mainly responsible for increase in the lead level in human body through inhalation,
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ingestion and dermal contact. Lead in the form of a toxin induces various biochemical,
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physiological and behavioral dysfunctions. Particularly liver, spleen, and kidney have been
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reported as key target sites for lead toxicity3. Virtually in all heavy metals lead is toxic
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abundantly to humans from thousands of years. On entering in our bodies with food, air and
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water lead induces toxicity by interacting with cellular compounds which contain sulfur, oxygen,
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or nitrogen elements2. Increased blood lead levels are primary diagnosis of lead toxicity.
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However, acute exposure to lead results in several malfunctioning such as neurobehavioral and
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neurological damage, cognitive dysfunction, hypertension, as well as renal impairment. Among
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the parts of the human body and systems hematopoietic, renal, reproductive, and central nervous
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system are more vulnerable toward the dangers from exposure to high level of lead4. According
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to Jalali et al. (2017), the elevation of malondialdehyde (MDA) level increases erythrocyte
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superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities along with rise in total
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leukocyte, lymphocyte and neutrophil counts resulting into microcytic anemia in the lead treated
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rats5. Chelation therapy is the conventional suggestion for low level lead poisoning with brain
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(encephalopathic) damage. However, the treatment with low-amount but for longer duration is
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still under investigation. Issues surrounding the assessment of body lead burden and the
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consequences of low-level environmental exposure are critical in the treatment of chronic
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diseases. Although co-administration of antioxidants such as natural, herbal, synthetic or another
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chelating agent have been reported to improve the effect of toxic metals5,6. It is required to
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develop preexisting or newer chelating agents to reap real benefit with the least side effects
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during combination therapy in association with those of antioxidants. In animal models, the
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clinical recoveries are possible to be done by the same. The present review article summarizes
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the recent account of lead toxicity in mammalian systems, targets, mechanisms of actions and
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possible amelioration using the synthetic chelators and plant products.
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2. SOURCES OF LEAD EXPOSURE
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Among the heavy metals, lead is highly persistent in nature. The various sources of lead in the
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environment include groundwater, soil, dust of metal ores, brass plumbing fixtures, several
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industrial activities, folk remedies, combustion of petroleum, manufacturing of lead-battery,
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paint industries, and mining processes contaminated food, and certain herbal products
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manufactured in combination with lead1. (Figure 1). Humans are continually exposed to lead
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from numerous sources such as contaminated air, water, soil, house dust and food via food chain
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and inhalation. In children, lead paints and lead chips are primary and major sources of lead
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intoxication. According to U.S. Department of Housing and Urban Development, about 38
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million houses in United States use lead-based paints. The report suggests that around 24 million
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of those houses comprise significant lead-based paint hazards, which also include deteriorating
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paints and/or dust or soil contamination at outside the home7. Manufacturing process of lead-
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based products may release as pollutants and mix with soil and water which enter in the body
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through food, water and air8. Inadvertent ingestion is another way of exposure to lead-
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contaminated soil, dust particles and lead-based paint. The growing population including
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children, infants in neonatal periods, and the fetus are most susceptible to lead poisoning9. In
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daycare centers and schools plumbing components containing lead contribute to significant
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amount of lead in drinking water. Also, the ceramics and food containers painted with lead-based
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paint / lead-containing glaze contribute to sufficient amount of lead (Figure 1). The lead
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containing occupational areas have higher levels of lead, so workers from these areas have been
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reported to get greater chances of lead-exposure. Some other sources of lead poisoning are
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manufacture of ammunition, batteries, ceramic glazes, circuit boards, caulking, sheet lead,
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solder, some brass and bronze plumbing, radiation shields, intravenous pumps, fetal monitors,
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and some surgical equipment and military equipment such as jet turbine engines, military
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tracking systems etc. (Figure.1). Workers have a greater risk to lead exposure at various
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construction sites10,11.
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Figure 1. Sources of lead in the environment.
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3. LEAD IN CELLULAR AND REDOX ENVIRONMENT
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The balance and stability between the generation of reactive nitrogen species (RNS), reactive
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oxygen species (ROS) and elimination of these species by antioxidant molecule and antioxidant
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defense system of the cell is known as the redox environment of the cells12 (Table 3). The
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production and removal of ROS influence the cellular redox environment. An environmental
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toxicant, lead involve in production of (ROS) during oxidative stress (OS)13. OS induced by lead
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toxicity is associated with several pathophysiological condition including oxidative damage to
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different body organs such as heart, kidneys, brain, and reproductive organs14. ROS are the
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products of cellular metabolism. The concentration of ROS molecules depends on concentrations
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and duration of xenobiotics exposure. ROS can be both beneficial and harmful to the tissues.
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Normally, ROS molecule functions as messengers in various cellular signaling and regulation of
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cellular processes, such as cell proliferation15 (Table 3).
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4. MECHANISM OF ACTION
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In 1965, the earlist paper related to lead mediated OS was published. In this investigation,
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several metals were found to enhance the rate of essential fatty acids oxidation. That time lead
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was reported to be ineffective. Many years later, it was observed that lead was reponsible for
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increase in lipid peroxidation as analysed by malondialdehy (MDA). Further, several researchers
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reported the lead induced lipid peroxidation in rat brain. A direct correlation has been recorded
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by Shafiq-ur-Rehman (1984) between increase in the lead concentration and the increase in lipid
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peroxidaton. Similarly, in the liver tissues similar effect was observed16. The mechanisms
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involved in lead-mediated OS primarily involves (Figure 2) damage to membrane and DNA of
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cell as well as damage to certain enzymes including catalase, GPx, SOD, and glucose-6-
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phosphate dehydrogenase (G6PD) and non-enzymatic antioxidant molecules including thiols
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(GSH) in mammalian systems17,18.
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A number of investigations have indicated the involvement of multifactorial mechanism in
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metal-induced toxicity (Figure 3). These multifactorial mechanisms can be associated to the OS,
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enzyme inhibition, DNA damage, and change in gene expression and adventitious like mimicry.
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Metal induced generation of free radical especially ROS are well known mechanism (Table 3)
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(Figure 3). The mechanisms that enable lead for induction of OS are not clearly mentioned
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because lead can not readily undergo valance change. The electron-sharing affinities of lead form
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covalent bonding with sulphydryl groups. Lead and GSH interaction is essential for its toxic
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response19. In case of signaling pathway, Lead mimics as calcium and binds with calmodulin
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protein (Ca2+-binding protein) that has been identified to inducing lead toxicity. The relative
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affinity of lead binding is higher than calcium20 (Figure 4). Different types of mechanisms have
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been proposed for lead medieted OS: (a) Direct effect of lead on cell membranes, (b) Lead-
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hemoglobin interactions, (c) δ-aminolevulinic acid (δ-ALA)–mediated generation of ROS, and
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(d) Effect of lead on the antioxidant defense system of cells.
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Figure 2. Overview of mechanism of action and molecular targets of lead. Lead exposure causes
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oxidative stress by increasing the level of free radicals and decreasing the antioxidant defense
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system inside the cell. Primarily, it involves damage to major biomolecules (such as lipid,
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protein and nucleic acids) leading to the altered cellular functions causing necrosis or cell death.
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5. BIOMOLECULAR PATHWAYS OF LEAD POISONING
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Lead toxicity can affect every organ system. Lead induces a broad range of biochemical,
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physiological, and genetic dysfunctions (Figure 3). It includes the ability of lead to inhibit /
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mimic the actions of Ca++ (calcium-dependent or similar processes can be affected) and also
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interact with some proteins (such as those with amine, carboxyl, phosphate and sulfhydryl,
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groups). Lead induced bimolecular consequences in living cells given as below:
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5.1. NEUROTOXICITY BY LEAD AND ITS ACTION
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Nervous system is one of the most sensitive targets of lead exposure. Generally, it causes
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neurotoxicity but decreases pediatric cognitive functions significantly. The excess generation of
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free radicals are also associated with neurotoxicity by causing perturbations in the brain
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functions. Since Lead efficiently crosses the blood brain barrier (BBB) and it easily substitutes
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calcium ions and thus, interrupts its intracellular activities by interfering with the regulatory
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actions of calcium in brain cells21. In children, long term exposure to lead may result in frequent
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occurrence of coma, seizures, and altered mental status.
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Several clinical studies are conducted on relationship of Lead poisoning and its effect on
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neurological development and functions. The outcome of these clinical reports significantly
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(P
