Elsevier

Toxicology

Volume 180, Issue 1, 30 October 2002, Pages 33-44
Toxicology

Antioxidant nutrients and lead toxicity

https://doi.org/10.1016/S0300-483X(02)00380-3Get rights and content

Abstract

Lead-induced oxidative stress contributes to the pathogenesis of lead poisoning for disrupting the delicate prooxidant/antioxidant balance that exists within mammalian cells. Production of reactive oxygen species (ROS) is increased after lead treatment in in vitro studies. In vivo studies suggest that lead exposure causes generation of ROS and alteration of antioxidant defense systems in animals and occupationally exposed workers. The mechanisms for lead-induced oxidative stress include the effect of lead on membrane, DNA, and antioxidant defense systems of cells. From low to high doses of lead exposure, there are different responses of lead-induced oxidative stress in various target sites including lung, blood vessels, testes, sperm, liver, and brain in epidemiological as well as animal studies. Therefore, reducing the possibility of lead interacting with critical biomolecules and inducing oxidative damage, or bolstering the cell's antioxidant defenses might be associated with the beneficial role of antioxidant nutrients through exogenous supplementation of antioxidant molecules. Although many researchers have investigated the benefit of antioxidants in preventing lead toxicity, the mechanisms of antioxidant nutrients being effective via rebalancing the impaired prooxidant/antioxidant ratio are not completely clear. Antioxidant nutrients including, vitamin E, vitamin C, vitamin B6, β-carotene, zinc, and selenium, are addressed in this review to discuss their beneficial role in lead-induced oxidative stress.

Introduction

Lead is a ubiquitous environmental and industrial pollutant that has been detected in almost all phases of environmental and biological systems. The quantity of lead used in the 20th century far exceeds the total consumed in all previous eras. This heavy use has caused local and global contamination of air, dust, and soil. Lead is known to induce a broad range of physiological, biochemical, and behavioral dysfunctions in laboratory animals and humans (Goyer, 1996, Ruff et al., 1996), including central and peripheral nervous systems (Bressler et al., 1999), haemopoietic system (De Silva, 1981), cardiovascular system (Khalil-Manesh et al., 1993), kidneys (Humphreys, 1991), liver (Sharama and Street, 1980) and male (Lancranjan et al., 1975) and female reproductive systems (Rom, 1980).

Generation of highly reactive oxygen species (ROS), such as superoxide radicals (O2radical dot), hydrogen peroxide (H2O2), hydroxyl radicals (radical dotOH) and lipid peroxides (LPO), in the aftermath of heavy metal ions are known to damage various cellular components including proteins, membrane lipids and nucleic acids (Halliwell and Gutteridge, 1989). Evidence indicates that transition metals, especially iron and copper, are able to produce ROS that result in lipid peroxidation, DNA damage, and depletion of cell antioxidant defense systems. The more recent finding of the oxidative damage caused by lead exposure of biological macromolecules suggested a new mechanism for an old problem. One current theory as to how lead exerts its toxic effects suggests that lead-induced oxidative stress contributes to the pathogenesis of lead poisoning by disrupting the delicate prooxidant/antioxidant balance that exists within mammalian cells (Lima-Hermes et al., 1991, Monterio et al., 1995). Some in vitro studies pointed to increased production of ROS after lead treatment (Ribarov and Bochev, 1982, Monterio et al., 1991). In vivo studies suggested that lead exposure might cause generation of ROS and alteration of antioxidant defense systems in animals (Lawton and Donaldson, 1991, Sandhir et al., 1994, Hsu et al., 1997) and workers (Ito et al., 1985, Solliway et al., 1996).

This review summarizes studies on lead-induced oxidative stress as well as the beneficial role of antioxidant nutrients on such stress. It will focus especially on reproductive toxicity and consider new work on the molecular genetic mechanisms of lead toxicity, and examine recent animal studies and epidemiological findings.

Section snippets

The mechanisms for lead-induced oxidative stress

An imbalance in the generation and removal of ROS in tissue and cellular components is known to cause damage to membranes, DNA, or proteins, and is generally called oxidative stress. The mechanisms for lead-induced oxidative stress include the effect of lead on membrane, DNA, and antioxidant defense systems of cells. On cell membrane, the presence of double bonds in the fatty acid weakens the CH bonds on the carbon atom adjacent to the double bonds and makes H removal easier. Therefore, fatty

Dose–response between lead exposure and oxidative stress

In pregnant women with low-levels of blood lead concentrations from 2.7 to 12.6 μg/dl, an inverse relationship was observed between blood lead levels (BLL) and serum levels of α-tocopherol and ascorbic acid (West et al., 1994). Blood levels of MDA, a product of lipid peroxidation, were strongly correlated with lead concentrations higher than 35 μg/dl (Bechara et al., 1993). From low to high doses of lead exposure, there were different responses of lead-induced oxidative stress in various target

Beneficial role of antioxidant nutrients on lead-induced oxidative stress

Oxidative stress can be partially implicated in lead toxicity. Therefore, reducing the possibility of lead interacting with critical biomolecules and bolstering the cell's antioxidant defenses might be associated with the beneficial role of antioxidant nutrients through exogenous supplementation of antioxidant molecules (Table 2). Although mechanisms of antioxidant nutrients being effective via rebalancing the impaired prooxidant/antioxidant ratio in abating lead toxicity are still not

Conclusion

Generation of highly reactive oxygen species in the aftermath of lead exposure may result in systematic mobilization and depletion of the cell's intrinsic antioxidant defenses. When formation of reactive oxygen intermediates outstrips the scavenging capacity of these antioxidant defense mechanisms, harmful free radicals accumulate and increase the likelihood of oxidative damage to critical biomolecules, such as enzymes, proteins, DNA, and membrane lipids. Several mechanisms have been proposed

Acknowledgements

This review was supported in part by the grants NSC89-2314-B-327-001 and NSC90-2621-Z006-005 from National Science Council, Republic of China.

References (96)

  • B.B. Gelman et al.

    The effect of lead on oxidative hemolysis and erythrocyte defense mechanisms in the rat

    Toxicol. Appl. Pharmacol.

    (1978)
  • R.A. Goyer et al.

    Ascorbic acid and EDTA treatment of lead toxicity in rats

    Life Sci.

    (1979)
  • H. Gurer et al.

    Can antioxidants be beneficial in the treatment of lead poisoning

    Free Radic. Biol. Med.

    (2000)
  • H. Gurer et al.

    Antioxidant effects of N-acetylcysteine and succimer in red blood cells from lead-exposed rats

    Toxicology

    (1998)
  • M. Hermes-Lima

    How do Ca2+ and 5-aminolevulinic acid-derived oxyradicals promote injury to isolated mitochondria

    Free Radic. Biol. Med.

    (1995)
  • M. Hermes-Lima et al.

    Damage to rat liver mitochondria promoted by δ-aminolevulinic acid-generated reactive oxygen species: connections with acute intermittent porphria and lead poisoning

    Biochim. Biophys. Acta

    (1991)
  • D.C. Hilderbrand et al.

    Effect of lead acetate on reproduction

    Am. J. Obstet. Gynecol.

    (1973)
  • J.M. Hsu

    Lead toxicity related to glutathione metabolism

    J. Nutr.

    (1981)
  • P.C. Hsu et al.

    Lead exposure causes generation of reactive oxygen species and functional impairment in rat sperm

    Toxicology

    (1997)
  • P.C. Hsu et al.

    Hydrogen peroxide induces premature acrosome reaction in rat sperm and reduces their penetration of zona pellucida

    Toxicology

    (1999)
  • D.J. Humphreys

    Effects of exposure to excessive quantities of lead on animals

    Br. Vet. J.

    (1991)
  • J.H.R. Kagi et al.

    Metallothionein, a cadmium and zinc containing protein from equine renal cortex

    J. Biol. Chem.

    (1961)
  • S.O. Knowles et al.

    Dietary modification of lead toxicity: effects on fatty acid and eicosanoid metabolism in chicks

    Comp. Biochem. Physiol.

    (1990)
  • N.A. Lachant et al.

    Inhibition of the pentose phosphate shunt by lead: a potential mechanism for hemolysis in lead poisoning

    Blood

    (1984)
  • C. McGowan

    Influence of vitamin B6 status on aspects of lead poisoning in rats

    Toxicol. Lett.

    (1989)
  • A. Mortensen et al.

    Relative stability of carotenoid radical cations and homologue tocopheroxyl radicals. A real time kinetic study of antioxidant hierarchy

    FEBS Lett.

    (1997)
  • A. Mortensen et al.

    The interaction of dietary carotenoids with radical species

    Arch. Biochem. Biophy.

    (2001)
  • L. Packer

    Protective role of vitamin E in biological systems

    Am. J. Clin. Nutr.

    (1991)
  • R.C. Patra et al.

    Antioxidant effects of α-tocopherol, ascorbic acid and l-methionine on lead induced oxidative stress to the liver, kidney and brain in rats

    Toxicology

    (2001)
  • S.R. Ribarov et al.

    Lead–hemoglobin interaction as a possible source of reactive oxygen species—a chemiluminescent study

    Arch. Biochem. Biophys.

    (1982)
  • A. Telfer et al.

    Isolated photosynthetic reaction center of photosystem II as a sensitizer for the formation of singlet oxygen. Detection and quantum yield determination using a chemical trapping technique

    J. Biol. Chem.

    (1994)
  • J.T. Zelikoff et al.

    Inhalation of particulate lead oxide disrupts pulmonary macrophage-mediated functions important for host defense and tumor surveillance in the lung

    Environ. Res.

    (1993)
  • A. Azzi et al.

    The protein kinase C family

    Eur. J. Biochem.

    (1992)
  • E.J.H. Bechara

    Oxidative stress in acute intermittent porphyria and lead poisoning may be triggered by 5-aminolevulinic acid

    Braz. J. Med. Biol. Res.

    (1996)
  • E.J.H. Bechara et al.

    A free radical hypothesis of lead poisoning and inborn porphyrias associated with 5-aminolevulinic acid overload

    Quim. Nova

    (1993)
  • J. Bressler et al.

    Mechanism of lead neurotoxicity

    Neurochem. Res.

    (1999)
  • M. Chiba et al.

    Indices of lead-exposure in blood and urine of lead-exposed workers and concentrations of major and trace elements and activities of SOD, GSH-Px and catalase in their blood

    Tohoku J. Exp. Med.

    (1996)
  • P. Cocco et al.

    Effects of short-term occupational exposure to lead on erythrocyte glucose-6-phosphate dehydrogenase activity and serum cholesterol

    J. Appl. Toxicol.

    (1995)
  • E.B. Dawson et al.

    Effect of ascorbic acid supplementation on blood lead levels

    J. Am. Coll. Nutr.

    (1997)
  • P.E. De Silva

    Determination of lead in plasma and studies on its relationship to lead in erythrocytes

    Br. J. Ind. Med.

    (1981)
  • M. Dhawan et al.

    Influence of thiamine and ascorbic acid supplementation on the antidotal efficacy of thiol chelators in experimental lead intoxication

    Arch. Toxicol.

    (1988)
  • Y. Ding et al.

    Lead promotes hydroxyl radical generation and lipid peroxidation in cultured aortic endothelial cells

    Am. J. Hypertens.

    (2001)
  • T. Douki et al.

    DNA alkylation by 4,5-dioxovaleric acid, the final oxidation product of 5-aminolevulinic acid

    Chem. Res. Toxicol.

    (1998)
  • N. Ercal et al.

    A role for oxidative stress in suppressing serum immunoglobulin levels in lead-exposed Fisher 344 rats

    Arch. Environ. Contam. Toxicol.

    (2000)
  • J.P. Farant et al.

    Biomonitoring lead exposure with ALAD activity ratios

    Int. Arch. Occup. Environ. Health

    (1982)
  • S.J. Flora et al.

    Preventive and therapeutic effects of thiamin, ascorbic acid and their combination in lead intoxication

    Acta Pharmacol. Toxicol.

    (1986)
  • S.J. Flora et al.

    Protective role of trace metals in lead intoxication

    Toxicol. Lett.

    (1982)
  • S.J. Flora et al.

    Thiamine and zinc in prevention or therapy of lead intoxication

    J. Intern. Med. Res.

    (1989)
  • Cited by (471)

    View all citing articles on Scopus
    View full text