These alterations play a prominent role in disease manifestations. Modulation of cellular thiols for protection against reactive oxygen species ROS has been used as a therapeutic strategy against lead poisoning. This review provides a comprehensive account of recent updates describing health effects of lead exposure, relevant biomarkers and mechanisms involved in lead toxicity. It also updates the readers about recent advances in chelation therapy and newer therapeutic strategies, like nanoencapsulation, to treat lead induced toxic manifestations.
Lead Pb is ubiquitous and one of the earliest metals discovered by the human race. Unique properties of lead, like softness, high malleability, ductility, low melting point and resistance to corrosion, have resulted in its widespread usage in different industries like automobiles, paint, ceramics, plastics, etc. This in turn has led to a manifold rise in the occurrence of free lead in biological systems and the inert environment. Lead is regarded as a potent occupational toxin and its toxicological manifestations are well known.
The non biodegradable nature of lead is the prime reason for its prolonged persistence in the environment. Human exposure to lead occurs through various sources like leaded gasoline, industrial processes such as lead smelting and coal combustion, lead-based paints, lead containing pipes or lead-based solder in water supply systems, battery recycling, grids and bearings, etc.
Although lead toxicity is a highly explored and comprehensively published topic, complete control and prevention over lead exposure is still far from being achieved. Lead toxicity is a particularly insidious hazard with the potential of causing irreversible health effects. Acute toxicity is related to occupational exposure and is quite uncommon.
It can be much more severe if not treated in time and is characterized by persistent vomiting, encephalopathy, lethargy, delirium, convulsions and coma Flora et al. Compared to other organ systems, the nervous system appears to be the most sensitive and chief target for lead induced toxicity Cory-Slechta, Both the central nervous system and the peripheral nervous system become affected on lead exposure. The effects on the peripheral nervous system are more pronounced in adults while the central nervous system is more prominently affected in children Brent, ; Bellinger, Encephalopathy a progressive degeneration of certain parts of the brain is a direct consequence of lead exposure and the major symptoms include dullness, irritability, poor attention span, headache, muscular tremor, loss of memory and hallucinations.
More severe manifestations occur at very high exposures and include delirium, lack of coordination, convulsions, paralysis, coma and ataxia Flora et al. Fetuses and young children are especially vulnerable to the neurological effects of lead as the developing nervous system absorbs a higher fraction of lead.
The proportion of systemically circulating lead gaining access to the brain of children is significantly higher as compared to adults Needleman et al. Children may appear inattentive, hyperactive and irritable even at low lead exposure. Children with greater lead levels may be affected with delayed growth, decreased intelligence, short-term memory and hearing loss. At higher levels, lead can cause permanent brain damage and even death Cleveland et al. There is evidence suggesting that low level lead exposure significantly affects IQs along with behavior, concentration ability and attentiveness of the child.
Repercussions of lead exposure on the peripheral nervous system have also been observed in the form of peripheral neuropathy, involving reduced motor activity due to loss of myelin sheath which insulates the nerves, thus seriously impairing the transduction of nerve impulses, causing muscular weakness, especially of the exterior muscles, fatigue and lack of muscular co-ordination Sanders et al.
Lead directly affects the hematopoietic system through restraining the synthesis of hemoglobin by inhibiting various key enzymes involved in the heme synthesis pathway. It also reduces the life span of circulating erythrocytes by increasing the fragility of cell membranes.
The combined aftermath of these two processes leads to anemia Guidotti et al. Anemia caused on account of lead poisoning can be of two types: hemolytic anemia , which is associated with acute high-level lead exposure, and frank anemia , which is caused only when the blood lead level is significantly elevated for prolonged periods Vij, Lead significantly affects the heme synthesis pathway in a dose dependent manner by downregulating three key enzymes involved in the synthesis of heme.
The initial and final steps of heme synthesis take place in the mitochondria, whereas the intermediate steps take place in the cytoplasm.
Lead inhibits the three aforementioned vital enzymes of this pathway but its effect on ALAD is more profound and its inhibition has been used clinically to gauge the degree of lead poisoning.
Inhibition of ferrochelatase results in increased excretion of coproporphyrin in urine and accumulation of protoporphyrin in erythrocytes EP. Moreover, inhibition of this enzyme results in the substitution of iron by zinc in the porphyrin ring forming zinc protoporphyrin ZPP. The concentration of ZPP thus gets increased, which can also be used as an indicator to monitor the level of lead exposure Jangid et al. Thus, the collective inhibition of these three key enzymes blocks the heme production via the heme synthesis pathway.
The mechanism responsible for shortening the life cycle of erythrocytes is not well understood. One of the earliest observed hematological effects of lead revealed basophilic stipplings of red blood cells presence of dense material in red blood cells , which is also a potential biomarker for the detection of lead poisoning. These aggregates are degradation products of ribonucleic acid Patrick, Renal functional abnormality can be of two types: acute nephropathy and chronic nephropathy.
Acute nephropathy is characterized functionally by an impaired tubular transport mechanism and morphologically by the appearance of degenerative changes in the tubular epithelium along with the occurrence of nuclear inclusion bodies containing lead protein complexes.
It does not cause protein to appear in the urine but can give rise to abnormal excretion of glucose, phosphates and amino acids, a combination referred to as Fanconi's syndrome. Chronic nephropathy on the other hand, is much more severe and can lead to irreversible functional and morphological changes. It is characterized by glomerular and tubulointerstitial changes, resulting in renal breakdown, hypertension and hyperuricemia Rastogi, Both chronic and acute lead poisoning causes cardiac and vascular damage with potentially lethal consequences including hypertension and cardiovascular disease Navas-Acien et al.
Other major disorders include ischemic coronary heart disease, cerebrovascular accidents and peripheral vascular disease. Although evidence of causal relationship of lead exposure and hypertension was reported, it applies only in cases of cardiovascular outcomes of lead toxicity Navas-Acien et al.
Lead causes a number of adverse effects on the reproductive system in both men and women. Common effects seen in men include: reduced libido, abnormal spermatogenesis reduced motility and number , chromosomal damage, infertility, abnormal prostatic function and changes in serum testosterone.
Women on the other hand, are more susceptible to infertility, miscarriage, premature membrane rupture, pre-eclampsia, pregnancy hypertension and premature delivery Flora et al.
Moreover, during the gestation period, direct influence of lead on the developmental stages of the fetus has also been reported Saleh et al. The primary site of lead storage in the human body are bones Renner, ; Silbergeld et al. There are two compartments in bones where lead is believed to be stored. The exchangeable pool present at the surface of bone and the non-exchangeable pool located deeper in the cortical bone. Lead can enter into plasma at ease from the exchangeable pool but can leave the non-exchangeable pool and move to the surface only when bone is actively being re-absorbed Patrick, Lead is probably the most extensively studied heavy metal.
Studies carried out in this field have reported the presence of various cellular, intracellular and molecular mechanisms behind the toxicological manifestations caused by lead in the body. Oxidative stress represents an imbalance between the production of free radicals and the biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage Flora, It has been reported as a major mechanism of lead induced toxicity. The antioxidant defenses of the body come into play to nullify the generated ROS.
The most important antioxidant found in cells is g lutathione GSH. It is a tripeptide having sulfhydryl groups and is found in mammalian tissues in millimolar concentrations. It is an important antioxidant for quenching free radicals Mates, After donating the electron, it readily combines with another molecule of glutathione and forms glutathione disulfide GSSG in the presence of the enzyme glutathione peroxidase GP X. Lead shows electron sharing capability that results in the formation of covalent attachments.
These attachments are formed between the lead moiety and the sulfhydryl groups present in antioxidant enzymes, which are the most susceptible targets for lead and which eventually get inactivated. Lead inactivates glutathione by binding to sulfhydryl groups present in it.
A few other notable antioxidant enzymes that are rendered inactive by lead include super oxide dismutase SOD and catalase CAT. Apart from targeting the sulfhydryl groups, lead can also replace the zinc ions that serve as important co-factors for these antioxidant enzymes and inactivates them Flora et al. Lipid peroxidation is another biomarker of oxidative stress and is one of the most investigated consequences of ROS on lipid membranes.
The generated free radical captures electrons from the lipids present inside the cell membranes and damages the cell. Apart from lipid peroxidation, lead also causes hemoglobin oxidation, which directly causes RBC hemolysis.
These elevated ALA levels generate hydrogen peroxide and superoxide radical and also interact with oxyhemoglobin, resulting in the generation of hydroxyl radicals Patrick, Progression of all the above mentioned mechanisms makes the cell extremely vulnerable to oxidative stress and may lead to cell death.
Significant effects have been found on various fundamental cellular processes like intra and intercellular signaling, cell adhesion, protein folding and maturation, apoptosis, ionic transportation, enzyme regulation, release of neurotransmitters, etc.
Garza et al. The ionic mechanism contributes principally to neurological deficits, as lead, after replacing calcium ions, becomes competent to cross the blood-brain barrier BBB at an appreciable rate. After crossing the BBB, lead accumulates in astroglial cells containing lead binding proteins. Toxic effects of lead are more pronounced in the developing nervous system comprising immature astroglial cells that lack lead binding proteins.
Lead easily damages the immature astroglial cells and obstructs the formation of myelin sheath, both factors involved in the development of BBB. Lead, even in picomolar concentration, can replace calcium, thereby affecting key neurotransmitters like protein kinase C, which regulates long term neural excitation and memory storage. It also affects the sodium ion concentration, which is responsible for numerous vital biological activities like generation of action potentials in the excitatory tissues for the purpose of cell to cell communication, uptake of neurotransmitters choline, dopamine and GABA and regulation of uptake and retention of calcium by synaptosomes.
This interaction between lead and sodium seriously impairs the normal functioning of the aforementioned sodium dependent processes Bressler et al. Preventive measures are preferred over the treatment regimens, considering the toxic effects of lead. This is due to the fact that once lead enters the body, it is almost impossible to remove it completely or to reverse its damaging effects on the body.
Guidotti and Ragain suggested a three-way measure as preliminary preventive approach towards lead toxicity. It includes Individual intervention , Preventive medicine strategy and Public health strategy. Preventive medicine strategy mainly aims at screening the blood levels of children that are at a high risk of lead exposure.
If lead is detected in blood, medical intervention is carried out with the aim to control undesirable outcomes of poisoning and prevent further accumulation of lead.
Public health strategy has a much larger sphere of influence and acts at a population level with a target to reduce the risk of lead exposure in habitable regions. Various preventive strategies have been suggested by the public health services for controlling lead.
The most important of them include: prohibition of setting up industries dealing with lead close to habitable areas and completely banning the use of lead where appropriate replacement is available. Apart from the above mentioned preliminary strategies, nutrition also plays an important role in prevention of lead induced toxicity.
Studies have shown that uptake of certain nutrients like mineral elements, flavonoids and vitamins can provide protection from the environmental lead as well as from the lead already present in the body.
Lead stimulated oxidative stress is a state that involves the generation of free radicals beyond the permissible limits, depleting at the same time the antioxidant reserves and thus hampering the ability of the biological system to reverse the resulting effects. Research findings have suggested that administration of various antioxidants can prevent or subdue various toxic effects of lead and generation of oxidative stress in particular. An antioxidant is a substance which, when present at a low concentration as compared to that of the oxidizable substrate, can prevent the oxidation of that substrate.
By inactivating the generated ROS at molecular level, thereby terminating the radical chain reaction chain breaking. By chelating lead and maintaining it in a redox state, which leads to its incompetency to reduce molecular oxygen.
Antioxidants may be broadly grouped according to their mechanism of action: primary or chain breaking antioxidants and secondary or preventive antioxidants. Primary antioxidants are compounds capable of scavenging free radicals that are responsible for initiation or propagation of the chain reaction through chain breaking mechanism Figure 4.
This is done by donating free electrons to ROS and lipid radicals present in the biological system and converting them into stable molecules.
This prevents or delays the oxidation process and prevents lipid peroxidation, which can cause membrane damage. Chain breaking mechanism of antioxidants. On the other hand, secondary antioxidants like low molecular weight polyphenols are those which mainly act by slowing down the rate of the oxidation reaction. The major difference between primary and secondary antioxidants is that the latter do not convert free radicals into stable molecules.
Naturally occurring antioxidants and their role in quenching free radicals generated in the body under various pathologic conditions have been an active area of research. Studies have revealed that antioxidants possess the ability of both preventing and curing the damage caused by the generation of free radicals in the body. Natural antioxidants can be categorized into enzymatic and non enzymatic. Enzymatic antioxidants like SOD, CAT, GP X are produced endogenously in the cells, whereas non enzymatic antioxidants like carotenoids, flavonoids, vitamins, minerals, etc.
The amount of antioxidants present under normal physiological conditions is just adequate to quench the free radicals that are generated at a normal physiological rate. Any further increment in the concentration of free radicals due to environmental or natural causes can cause an imbalance between the free radicals and antioxidants, leading to oxidative stress Blokhina et al.
This is where the role of exogenous antioxidants becomes important. They are taken through the diet or in the form of supplements to maintain the homeostasis between free radicals and antioxidants and thus prevent various deleterious effects, like heavy metal toxicity, inflammation, cancer, aging, cardiovascular and brain disorders Willcox et al.
Under normal physiological conditions, there is a balance between free radicals and antioxidants and any deviation from it can cause oxidative stress leading to cell death. It has been reported that those who take an antioxidant rich diet are at the forefront of reaping various health benefits. To boost antioxidant levels, food is always favored over supplements mainly because it contains thousands of antioxidants, in contrast to supplements, which are generally rich in a single or a few antioxidants.
This review will now incorporate a detailed study of some natural antioxidants that have been investigated and put forth for the treatment of lead induced oxidative stress. The role of vitamins particularly B, C and E has been found to be extremely significant and competitive in fighting toxicological manifestations of lead poisoning.
The role of various prominent vitamins in preventing lead toxicity has been discussed. Vitamin B6 pyridoxine and vitamin B1 thiamine are reported to have essential characteristics that can cure the deleterious effects of lead toxicity.
Pyridoxine is an important co-factor which participates in the metabolic trans-sulfuration pathway which is responsible for the synthesis of cysteine from dietary methionine.
Chelation of lead by vitamin B6 could be attributed to the presence of the ring in the nitrogen atom or to the interference of vitamin B6 with the absorption of lead. Vitamin B1 thiamine has also been reported to exert protective efficacy against short-term implications of lead poisoning. Senapati et al. They revealed a significant decrement in the levels of lead in liver and kidney. Ascorbic acid is probably the most widely studied vitamin when it comes to the prevention of lead induced oxidative stress.
A recent study done by Chang et al. They reported that introduction of ascorbic acid during pregnancy and lactation caused to some extent amelioration of oxidative stress in the developing hippocampus. Shan et al. Co-administration of ascorbic acid and thiamine reverted the oxidative stress in a concentration dependent manner, as well as DNA damage and apoptosis induced by lead in rat liver cells Wang et al.
Supplementation of ascorbic acid in combination with silymarin was able to reduce acute hepatotoxic lead toxicity Shalan et al. Vitamin E is a fat soluble vitamin with numerous biological functions Flora, It possesses powerful anti-oxidative properties, operative in the membrane to prevent lipid peroxidation by obstructing the free radical chain reaction.
Sajitha et al. Vitamin E was also found to be helpful in restoring thyroid dysfunction by maintaining the hepatic cell membrane architecture disrupted indirectly by lead induced lipid peroxidation. Effect of vitamin E in combination with other antioxidants has been found to be more pronounced than its individual administration. Flora et al. Flavonoids are naturally occurring polyphenolic compounds.
They are the main constituents of fruits, vegetables and certain beverages Youdim et al. The anti-oxidative nature of flavonoids has been extensively investigated. These compounds, like other anti-oxidants, can cure or prevent oxidative stress by chelating redox active metal ions and also by terminating the free radical chain reaction Terao, ; Rice-Evans, The capacity of flavonoids to act as antioxidants depends upon their molecular structure Figure 6. Their general structure includes a diphenylpropane moiety composed of two or more aromatic rings A and B , each having at least one aromatic hydroxyl group connected via a carbon chain.
The chain consists of three carbons that combine with an oxygen and two carbons of one of the aromatic rings A ring to form a third 6-member ring C ring known as the pyran ring Larson et al. The metal chelating ability of flavonoids arises from the appropriate positioning of the functional groups that include both the hydroxyl groups of ring-B and the 5-hydroxy group of ring-A.
Another structural feature that contributes to the anti-oxidative nature is the presence of 2, 3 double bond in conjugation with a 4-oxo group in the C-ring Heim et al. Quercetin is a ubiquitously distributed and comprehensively explored bioflavonoid.
Dietary sources of quercetin include fruits, vegetables and tea. The presence of multiple hydroxyl groups in its chemical structure and conjugated electrons account for its antioxidant and metal chelating property Figure 7.
These hydroxyl groups along with the carbonyl group easily donate electrons by undergoing resonance and stabilize free radicals that can initiate lipid peroxidation Beecher, Liu et al.
TUNEL assay confirmed the inhibition of lead induced apoptosis in the rat kidney. Hu et al. All of these showed significant improvement after treatment with quercetin. Reduction in hippocampal lead concentration was also reported. Thus, the medicinal and therapeutic properties of quercetin, along with its low toxicological profile, has made it a very promising drug in the field of heavy metal toxicity.
Alpha lipoic acid is an antioxidant synthesized in small amounts in the human body. It is also present in certain foods, including carrots, beets, spinach, potatoes and red meat Durrani et al. Its antioxidant activity tends to act in dual ways: first it attacks ROS and prevents the formation of lipid peroxides, and second, it can replenish and regenerate other antioxidants like vitamin C and E Haleagrahara et al.
Lipoic acid has mostly been used in combination with other chelating agents like 2,3-dimercaptosuccinic acid DMSA , due to the fact that lipoic acid itself does not have metal chelating ability but it can consistently tackle the generated oxidative stress. Sivaprasad et al. Lipoic acid was found to be more effective in removing lead from the brain compared to any other organs liver, kidneys and other soft tissues Pande and Flora.
The ability of herbal antioxidants to act as useful clinical medicine is due to their low cost and few side effects. Even below this level there is an inverse correlation between blood lead concentration and IQ scores. Thus, lead toxicity continues to be a matter of concern. Lead may be mobilized from the maternal skeleton during pregnancy and readily crosses the placental barrier. Hence lead exposure can begin in utero.
Similar to neurotoxicity caused by methylmercury, the developing nervous system of the fetus and infants is extremely susceptible to lead toxicity.
Molecular pathology B. Cellular pathology C. Tissular pathology D. General pathology E. Pathology by systems F. Pathology by regions G. Tumoral pathology H. Case records K.
Info - Admin Resources in pathology Technical section. The toxicity of lead is related to its multiple biochemical effects: High affinity for sulfhydryl groups. General pathology Ageing Blood and immunity Endocrine systemic anomalies Environmental and occupational diseases Genetic and developmental anomalies Infectious diseases Nutritional diseases Therapy, Toxics and drugs Vascular pathology.
Also in this section glyphosate kepone occupational diseases environmental diseases environment smoking-associated cancers cellular response to UVB radiation References Ultraviolet damage, DNA repair DNA photoproducts signature of environmental exposure. Blood 11 , Granick, J. Sassa, S. Granick, R. Levere, and A. Kappas: Studies in lead poisoning. Correlation between the ratio of activated to inactivated delta-amino levulinic acid dehydratase of whole blood and the blood lead level.
Griggs, R. Haider, G. Bleivergiftung bei Regenbogenforellen Salmo gairdneri Rich. Hernberg, S. Lancet 1 , 63 Nikkanen, G. Mellin, and H. Lilius: Delta-aminolevulinic acid dehydratase as a measure of lead exposure. Health 21 , Tola, J. Nikkanen, and S. Valkonen: Erythrocyte delta-amino-levulinic acid dehydratase in new lead exposure. Health 25 , Nordberg ed. Amsterdam-Oxford-New York: Elsevier Hodson, P. Board Can. Blunt, D. Spry, and K. Austen: Evaluation of erythrocyte delta-amino levulinic acid dehydratase activity as a short-term indicator in fish of a harmful exposure to lead.
Holcombe, G. Benoit, E. Leonard, and J. McKim: Long-term effects of lead exposure on three generations of brook trout Salvelinus fontinalis. Jackim, E. Jordan, H. Larsson: The effect of cadmium on the hematology and on the activity of delta-aminolevulinic acid dehydratase ALA-D in blood and hematopoietic tissues of the flounder, Pleuronectes flesus L. Lauwerys, R. Buchet, and H. Roels: Comparative study of effect of inorganic lead and cadmium on blood delta-aminolevulinate dehydratase in man.
Millar, J. Cumming, V. Battistini, F. Carswell, and A. Goldberg: Lead and deltaaminolevulinic acid dehydratase levels in mentally retarded children and in lead-poisoned suckling rats. Lancet 2 ,
0コメント