The delta-aminolevulinic acid dehydratase (ALAD) polymorphism and bone and blood lead levels in community-exposed men: the Normative Aging Study.

Recent research has indicated that a polymorphic variant of delta-aminolevulinic acid dehydratase (ALAD) may influence an individual's level of lead in bone and blood and, as a result, may also influence an individual's susceptibility to lead toxicity. In this study, we investigated whether this ALAD polymorphism is associated with altered levels of lead in bone and blood among 726 middle-aged and elderly men who had community (nonoccupational) exposures to lead. We measured levels of blood and bone lead by graphite furnace atomic absorption spectroscopy and a K X-ray fluorescence (KXRF) instrument, respectively. We determined the ALAD MspI polymorphism in exon 4 by a polymerase chain reaction restriction fragment length polymorphism (RFLP). Of the 726 subjects, 7 (1%) and 111 (15%) were, respectively, homozygous and heterozygous for the variant allele. The mean (SD) of blood lead (micrograms per deciliter), cortical bone (tibia) lead (micrograms per gram), and trabecular bone (patella) lead (micrograms per gram) were 6.2 (4.1), 22.1 (13.5), and 31.9 (19.5) in subjects who did not have the variant allele (ALAD 1-1), and 5.7 (4.2), 21.2 (10.9), and 30.4 (17.2) in the combined subjects who were either heterozygous or homozygous for the variant allele (ALAD 1-2 and ALAD 2-2). In multivariate linear regression models that controlled for age, education, smoking, alcohol ingestion, and vitamin D intake, the ALAD 1-1 genotype was associated with cortical bone lead levels that were 2.55 microg/g [95% confidence interval (CI) 0.05-5.05] higher than those of the variant allele carriers. We found no significant differences by genotype with respect to lead levels in trabecular bone or blood. In stratified analyses and a multivariate regression model that tested for interaction, the relationship of trabecular bone lead to blood lead appeared to be significantly modified by ALAD genotype, with variant allele carriers having higher blood lead levels, but only when trabecular bone lead levels exceeded 60 microg/g. These results suggest that the variant ALAD-2 allele modifies lead kinetics possibly by decreasing lead uptake into cortical bone and increasing the mobilization of lead from trabecular bone.

[1]  R. Desnick,et al.  Delta-aminolevulinic acid dehydratase polymorphism: influence on lead levels and kidney function in humans. , 1997, Archives of environmental health.

[2]  Howard Hu,et al.  Bone lead as a new biologic marker of lead dose: recent findings and implications for public health. , 1998, Environmental health perspectives.

[3]  G. Battistuzzi,et al.  δ‐aminolevulinate dehydrase: a new genetic polymorphism in man , 1981, Annals of human genetics.

[4]  C. M. Smith,et al.  A polymorphism in the delta-aminolevulinic acid dehydratase gene may modify the pharmacokinetics and toxicity of lead. , 1995, Environmental health perspectives.

[5]  R. Desnick,et al.  Lead Binding to δ-Aminolevulinic Acid Dehydratase (ALAD) in Human Erythrocytes , 1997 .

[6]  Howard Hu,et al.  Attentional correlates of dentin and bone lead levels in adolescents. , 1994, Archives of environmental health.

[7]  R. Desnick,et al.  Human delta-aminolevulinate dehydratase: nucleotide sequence of a full-length cDNA clone. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Howard Hu,et al.  Automated bone lead analysis by K-x-ray fluorescence for the clinical environment. , 1990, Basic life sciences.

[9]  J. Angerer,et al.  Polymorphism of delta-aminolevulinic acid dehydratase in lead-exposed workers , 1986, International archives of occupational and environmental health.

[10]  W. Stewart,et al.  Associations of delta-aminolevulinic acid dehydratase genotype with plant, exposure duration, and blood lead and zinc protoporphyrin levels in Korean lead workers. , 1995, American journal of epidemiology.

[11]  A. Rotnitzky,et al.  The relationship of bone and blood lead to hypertension. The Normative Aging Study. , 1996, JAMA.

[12]  R. Desnick,et al.  The delta-aminolevulinate dehydratase polymorphism: higher blood lead levels in lead workers and environmentally exposed children with the 1-2 and 2-2 isozymes. , 1991, Environmental research.

[13]  A. Onalaja,et al.  Genetic susceptibility to lead poisoning. , 2000, Environmental health perspectives.

[14]  C E Webber,et al.  Effect of the delta-aminolevulinate dehydratase polymorphism on the accumulation of lead in bone and blood in lead smelter workers. , 1998, Environmental research.

[15]  B. Alexander,et al.  Interaction of blood lead and delta-aminolevulinic acid dehydratase genotype on markers of heme synthesis and sperm production in lead smelter workers. , 1998, Environmental health perspectives.

[16]  A. Rotnitzky,et al.  Determinants of bone and blood lead levels among community-exposed middle-aged to elderly men. The normative aging study. , 1996, American journal of epidemiology.

[17]  Albert Damon,et al.  The Normative Aging Study: An Interdisciplinary and Longitudinal Study of Health and Aging , 1972 .

[18]  P. Vokonas,et al.  Electrocardiographic conduction disturbances in association with low-level lead exposure (the Normative Aging Study). , 1998, The American journal of cardiology.

[19]  J. Schwartz,et al.  Relation of nutrition to bone lead and blood lead levels in middle-aged to elderly men. The Normative Aging Study. , 1998, American journal of epidemiology.

[20]  R. Desnick,et al.  Molecular characterization of the human delta-aminolevulinate dehydratase 2 (ALAD2) allele: implications for molecular screening of individuals for genetic susceptibility to lead poisoning. , 1991, American journal of human genetics.