The δ-aminolevulinate dehydratase polymorphism: Higher blood lead levels in lead workers and environmentally exposed children with the 1–2 and 2-2 isozymes

Wetmur, James G.; Lehnert, G.; Desnick, Robert J.

doi:10.1016/s0013-9351(05)80001-5

Cited by 147 publications

(128 citation statements)

References 43 publications

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“…The results of the two completed studies demonstrating a relationship between blood lead levels and ALAD phenotype (29) (27). The results were not changed in a reanalysis excluding these children.…”

Section: Humanl Studiesmentioning

confidence: 98%

“…To date only two populations have been studied (double-blind) for blood lead and ALAD phenotype (29 (33). The analysis of the genome structure of human ALAD, necessary for constructing transgenic mice expressing human ALAD, is illustrated in Figure 1.…”

Section: Human Studiesmentioning

confidence: 99%

“…The existence of this frequent polymorphism in a gene whose product was implicated in the pathogenesis of lead toxicity suggested the potential for a genetically determined differential susceptibility. We determined the ALAD isozyme types of 1278 blood samples from children subjected to low-level environmental lead exposure in New York City (28,29). The blood lead level, measured by the New York City Lead Screening Program, and the ALAD isozyme phenotype were determined in a double-blind fashion.…”

Section: Introductionmentioning

confidence: 99%

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Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden.

Wetmur

1994

Environ Health Perspect

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&Aminolevulinate dehydratase (ALAD) is the second enzyme in the heme biosynthesis pathway. ALAD is a zinc metalloenzyme, and its inhibition by lead substitution for zinc is one of the most sensitive indicators of blood-lead accumulation, a measure of recent lead exposure. Stoichiometry calculations indicate that a significant portion of blood lead is stored in ALAD. Human ALAD exhibits a charge polymorphism, with about 20% of Caucasians expressing the rarer ALAD2 allele. Human ALAD1 and ALAD2 cDNAs and the 16-kb ALAD gene have been cloned and sequenced. A simple polymerase chain reaction test has been established and validated for determining ALAD genotypes. Two population studies have indicated that lead-exposed individuals with the ALAD allele have blood-lead levels about 10 pg/dl greater than similarly exposed individuals carrying only the ALAD1 allele. Ongoing work is directed toward determining the biochemistry underlying the allele-specific accumulation of blood lead, and toward determining the contribution of human ALAD genotype to lead accumulation in other tissues in transgenic mouse models and to final lead deposition in bone in both mouse and man. -Environ Health Perspect 102(Suppl 3): 215-219 (1994)

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Section: Humanl Studiesmentioning

confidence: 98%

Section: Human Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden.

Wetmur

1994

Environ Health Perspect

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“…For example, lead is known to bind to the enzyme aminolevulinic acid dehydratase (ALAD), and the absorption of lead is inversely related to calcium stores and dietary vitamin D intake (Chisolm et al 1985;Mahaffey et al 1986). Genetic variants in the ALAD and vitamin D receptor genes have been associated with lead exposure biomarkers (Hu et al 2001;Schwartz et al 2000aSchwartz et al , 2000bSmith et al 1995;Wetmur et al 1997).…”

mentioning

confidence: 99%

Association between hemochromatosis genotype and lead exposure among elderly men: the normative aging study.

Wright

Silverman

Schwartz

et al. 2004

Environ Health Perspect

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Because body iron burden is inversely associated with lead absorption, genes associated with hemochromatosis may modify body lead burden. Our objective was to determine whether the C282Y and/or H63D hemochromatosis gene (HFE) is associated with body lead burden. Patella and tibia lead levels were measured by K X-ray fluorescence in subjects from the Normative Aging Study. DNA samples were genotyped for C282Y and H63D using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). A series of multivariate linear regression models were constructed with bone or blood lead as dependent variables; age, smoking, and education as independent variables; and C282Y or H63D as independent risk factors and/or effect modifiers. Of 730 subjects, 94 (13%) carried the C282Y variant and 183 (25%) carried the H63D variant. In the crude analysis, mean tibia, patella, and blood lead levels were consistently lower in carriers of either HFE variant compared with levels in subjects with wild-type genotypes. In multivariate analyses that adjusted for age, smoking, and education, having an HFE variant allele was an independent predictor of significantly lower patella lead levels (p < 0.05). These data suggest that HFE variants have altered kinetics of lead accumulation after exposure. Among elderly men, subjects with HFE variants had lower patella lead levels. These effects may be mediated by alterations in lead toxicokinetics via iron metabolic pathways regulated by the HFE gene product and body iron stores.

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“…Th e c u rvat u re can be described by a model based on limited binding capacity for lead-binding proteins [8,9], and the binding capacity in such a model fits well with the erythrocytic concentration of ALAD [8]. iii) It has been suggested that a genetic polymorphism in the human ALAD gene may cause certain individuals to be more sensitive to lead toxicity than others [10][11][12]. The considerable binding of lead to ALAD may play an important role in the mechanism behind the influence of the ALAD polymorphism on lead toxicity.…”

Section: Lead-binding Proteins In Human Erythrocytesmentioning

confidence: 89%

Lead-binding proteins - a way to understand lead toxicity?

Bergdahl¹

1998

Analusis

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The δ-aminolevulinate dehydratase polymorphism: Higher blood lead levels in lead workers and environmentally exposed children with the 1–2 and 2-2 isozymes

Cited by 147 publications

References 43 publications

Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden.

Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden.

Association between hemochromatosis genotype and lead exposure among elderly men: the normative aging study.

Lead-binding proteins - a way to understand lead toxicity?

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