Superfund Research Program
Genetic Susceptibility to Lead Toxicity
Of all the hazardous substances found on Superfund sites, lead is one of the best understood in terms of its toxic effects in the human body. Lead is a potent neurotoxin in humans. Exposure to small amounts of the metal during the early stages of human development has been associated with impaired cognitive development and learning disabilities in young children. At any age, elevated levels of lead in the body can cause degeneration of cells in the peripheral nervous system, which can lead to a loss of muscular coordination and motor control. In addition to its well-known neurotoxicity, lead is a hematotoxin; it can impair the production of red blood cells by blocking synthesis of the heme molecule. Lead can also irreversibly damage the kidney at high doses. Even with all the knowledge we have about lead's adverse health effects, there are still gaps in our understanding of lead's toxicity in the human body.
One area of incomplete understanding concerns individual variation in response to lead exposure. The differential response of individuals to lead has been associated with a genetic polymorphism in the second enzyme of the heme synthesis pathway, delta-aminolevulinic acid dehydratase (ALAD). Generally speaking, genetic polymorphism is the occurrence of two or more forms (alleles) of the same gene in a population and it is a major cause of variation in human response to environmental contaminants. ALAD is polymorphic because it occurs in two major forms in humans, ALAD-1 and ALAD-2, which happen to differ by only one base pair at the gene level. While the two enzymes are similar functionally -- they both condense two molecules of aminolevulinic acid to produce a precursor of the heme molecule -- their slight structural difference appears to greatly modify the disposition of lead in the body. In particular, the variant form of the enzyme, ALAD-2, has been associated with elevated blood lead levels in children and adults. Because the exact mechanism of this biological effect is not known, it is not clear whether ALAD-2 enhances or reduces the ultimate toxicity of lead.
Scientists in the Harvard University Superfund Basic Research Program are collaborating with investigators at Johns Hopkins University and Soonchunhyang University (Republic of Korea) to further define the relationship between ALAD polymorphism and susceptibility to the toxic effects of lead exposure. The researchers are testing the hypothesis that the ALAD-2 enzyme is protective of lead toxicity. They are also interested in elucidating whether polymorphism in the ALAD gene is associated with alterations in the uptake and distribution of lead in the body.
To examine these issues the researchers studied a group of lead-exposed battery workers in Korea. A molecular DNA technique was used to identify which one of the three ALAD genotypes (ALAD 1-1, ALAD 1-2, and ALAD 2-2) each subject had. The researchers confirmed that the variant genotype is associated with higher blood lead levels in exposed workers. A new finding by this group showed that variant gene carriers with the ALAD 1-2 genotype also had lower serum concentrations of aminolevulinic acid, which is thought to be responsible for some of the neurotoxic effects associated with lead. Aminolevulinic acid is known to accumulate in the bloodstream upon lead exposure due to lead's inhibition of ALAD activity. What these results suggest is that workers with the ALAD 1-2 genotype may be protected from some of neurotoxic effects of lead exposure that are due to elevated aminolevulinic acid levels in the bloodstream.
The researchers also investigated whether ALAD genotype modified levels of bioavailable lead in the study population. Lead bioavailability was determined by measuring the amount of the metal that was excreted in the urine after administration of a chelating agent known as dimercaptosuccinic acid (DMSA). This orally administered agent preferentially removes lead from soft tissue storage sites such as the kidney and liver. What the researchers found is that DMSA chelatable levels of lead varied by ALAD genotype. Subjects with ALAD 1-2 had significantly lower concentrations of DMSA chelatable lead excreted in the urine than subjects with ALAD 1-1 who had similar blood lead concentrations, exposure durations, and ages. This data provides evidence that ALAD genotype may modify the retention and deposition of lead in the body.
These studies are significant for providing a better understanding of how ALAD polymorphism modifies individual response to lead exposures. While the ALAD polymorphism has been associated for some time with increased blood lead levels, the results of these two studies indicate a much more complicated relationship between ALAD genotype and the ultimate fate and toxicity of lead in the body. The findings show that the enzyme's polymorphism may modify not only the uptake and distribution of lead in the body, but also the neurotoxic effects of lead that are mediated by aminolevulinic acid.
In addition to being a priority pollutant on Superfund hazardous waste sites, lead is a major public health problem in the United States with chronic exposures to low levels of lead being an environmental reality. Lead poisoning also remains one of the most significant environmental hazards for young children, while an estimated one million adult workers are still exposed to excess amounts of lead in over 100 different occupations. Because people vary in their response to lead exposures, elucidating the factors that affect individual susceptibility to lead toxicity is crucial to setting environmental and occupational standards that are protective of all members of society.
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To learn more about this research, please refer to the following sources:
- Schwartz BS, Lee B, Stewart WF, Ahn KD, Kelsey KT, Bressler JP. 1997. Associations of subtypes of hemoglobin with delta-aminolevulinic acid dehydratase genotype and dimercaptosuccinic acid-chelatable lead levels. Arch Environ Health 52(2):97-103. PMID:9124882
- Schwartz BS, Lee B, Stewart WF, Sithisarankul P, Strickland PT, Ahn KD, Kelsey KT. 1997. delta-Aminolevulenic acid dehydratase genotype modifies four hour urinary lead excretion after oral administration of dimercaptosuccinic acid. Occup Environ Med 54(4):241-246. doi:10.1136/oem.54.4.241 PMID:9166129
- Sithisarankul P, Schwartz BS, Lee B, Kelsey KT, Strickland PT. 1997. Aminolevulenic acid dehydratase genotype mediates plasma levels of the neurotoxin, 5-aminolevulenic acid, in lead-exposed workers. Am J Ind Med 32(1):15-20. PMID:9131207
- Smith CM, Wang X, Hu H, Kelsey KT. 1995. A polymorphism in the δ-aminolevulinic acid dehydratase gene may modify the pharmacokinetics and toxicity of lead. Environ Health Perspect 103:248-253. PMID:7768225
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