ALAD
Delta-aminolevulinic acid dehydratase (EC 4.2.1.24) (ALADH) (Porphobilinogen synthase)
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Cumulative exposure to lead is associated with cardiovascular outcomes. Polymorphisms in the δ-aminolevulinic acid dehydratase (ALAD), hemochromatosis (HFE), heme oxygenase-1 (HMOX1), vitamin D receptor (VDR), glutathione S-transferase (GST) supergene family (GSTP1, GSTT1, GSTM1), apolipoprotein E (APOE),angiotensin II receptor-1 (AGTR1) and angiotensinogen (AGT) genes, are believed to alter toxicokinetics and/or toxicodynamics of lead. We assessed possible effect modification by genetic polymorphisms in ALAD, HFE, HMOX1, VDR, GSTP1, GSTT1, GSTM1, APOE, AGTR1 and AGT individually and as the genetic risk score (GRS) on the association between cumulative lead exposure and incident coronary heart disease (CHD) events. We used K-shell-X-ray fluorescence to measure bone lead levels. GRS was calculated on the basis of 22 lead-related loci. We constructed Cox proportional hazard models to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CHD. We applied inverse probability weighting to account for potential selection bias due to recruitment into the bone lead sub-study. Significant effect modification was found by VDR, HMOX1, GSTP1, APOE, and AGT genetic polymorphisms when evaluated individually. Further, the bone lead-CHD associations became larger as GRS increases. After adjusting for potential confounders, a HR of CHD was 2.27 (95%CI: 1.50-3.42) with 2-fold increase in patella lead levels, among participants in the top tertile of GRS. We also detected an increasing trend in HRs across tertiles of GRS (p-trend = 0.0063). Our findings suggest that lead-related loci as a whole may play an important role in susceptibility to lead-related CHD risk. These findings need to be validated in a separate cohort containing bone lead, lead-related genetic loci and incident CHD data.
MeSH Terms
- Aged
- Aging
- Bone and Bones
- Coronary Disease
- Environmental Exposure
- Female
- Genetic Predisposition to Disease
- Humans
- Lead
- Male
- Middle Aged
- Polymorphism, Genetic
The aim of this study was to explore therapeutic efficiency of succimer used with calcium and ascorbic acid in the treatment of mildly lead-poisoned mice and preschool children. Mice were exposed to lead by drinking water, and then treated with saline solution, 50mg/kg body weight (b.w.) succimer, 100mg/kg b.w. succimer, or 50mg/kg b.w. succimer plus calcium and ascorbic acid by gavage. Seventy-two children aged 48-72 months were randomly assigned into combined treatment or nutritional intervention group. Lead levels in blood and bone were analyzed by atomic absorption spectrophotometry. Activities of aminolevulinic acid dehydratase (ALAD) in blood were determined by colorimetric method. Results of animal experiment showed that succimer used alone could reduce lead levels in blood and bone and reverse activities of ALAD in blood, however, a better therapeutic efficiency in mobilizing bone lead could be achieved by succimer used with calcium and ascorbic acid. Findings from the clinical study showed that reduction of blood lead levels (BLLs) between the end and initiation of therapy in the combined treatment group was significantly greater than that in the nutritional intervention group. Percentage of children with BLLs less than 10μg/dL at the end of therapy and the eighth week after therapy in the combined treatment group was significantly higher than that in the nutritional intervention group. In conclusion, combined use of succimer with calcium and ascorbic acid seemed to be a choice in the treatment of mildly lead poisoned children.
MeSH Terms
- Aging
- Animals
- Ascorbic Acid
- Bone and Bones
- Calcium Carbonate
- Chelating Agents
- Child
- Child, Preschool
- Colorimetry
- Environmental Exposure
- Female
- Free Radical Scavengers
- Humans
- Lead
- Lead Poisoning
- Male
- Mice
- Porphobilinogen Synthase
- Succimer
We evaluated the modifying influence of a delta-aminolevulinic acid dehydratase (ALAD) polymorphism on the relation between lead burden and cognition among older men. Information on ALAD genotype, lead measurements, potential confounders, and cognitive testing was collected from 982 participants. For each cognitive test and lead biomarker, we fit separate multiple linear regression models, which included an interaction term for ALAD genotype and the lead biomarker and adjusted for potential confounders. With higher levels of tibia lead, ALAD 1-2/2-2 carriers exhibited worse performance on a spatial copying test in comparison with ALAD 1-1 carriers (P interaction = 0.03). However, there was no consistent pattern of an ALAD genotype-lead interaction for the other tests. The results provide some evidence that ALAD genotype may modify the relation between lead and cognition among older men with low lead burden. However, future work in this area is needed to confirm these suggestive findings.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Body Burden
- Bone and Bones
- Cognition Disorders
- Enzymes
- Humans
- Lead
- Lead Poisoning
- Male
- Massachusetts
- Middle Aged
- Polymorphism, Genetic
- Porphobilinogen Synthase
- United States
- United States Department of Veterans Affairs
- Young Adult
In this study we investigated whether a known delta-aminolevulinic acid dehydratase (ALAD) exon 4 polymorphism has a modifying effect on the association of blood or bone lead level with uricemia and indices of renal function among middle-aged and elderly men. We performed a cross-sectional study of subjects who participated between 1991 and 1995 in the Department of Veterans Affairs Normative Aging Study. Information on blood lead levels, bone lead levels (measured by K-shell X-ray fluorescence), serum uric acid, serum creatinine, estimated creatinine clearance, and ALAD polymorphism status was available in 709 subjects. Regression models were constructed to examine the relationships of serum uric acid, serum creatinine, and estimated creatinine clearance to blood or bone lead level, stratified by genotype. We also adjusted for age, body mass index, blood pressure, smoking, alcohol consumption, and ingestion of analgesic medications (n = 638). Of the 709 subjects, 7 (1%) and 107 (15%) were homozygous and heterozygous for the variant (ALAD-2) allele, respectively. The mean (range) serum uric acid and creatinine levels were 6.5 (2.9-10.6) and 1.2 (0.6-2.5) mg/dL. No significant differences were found in serum uric acid, serum creatinine, or estimated creatinine clearance by ALAD genotype. However, after adjusting for other potential confounders, we found a significant linear relationship between serum uric acid and patella bone lead (p = 0.040) among the ALAD 1-2/2-2 genotype individuals above a threshold patellar lead level of 15 micro g/g. In contrast, among the wild-type (ALAD 1-1) individuals, there was a suggestion of a significant linear relationship of serum uric acid with patella bone lead (p = 0.141), but only after a threshold of 101 micro g/g. There was evidence of a significant (p = 0.025) interaction of tibia lead with genotype (ALAD 1-1 vs. ALAD 1-2/2-2) regarding serum creatinine as an outcome, but in the same linear regression model tibia lead alone was not a significant predictor of serum creatinine. Conversely, for estimated creatinine clearance, patella lead, but not the interaction of patella lead with genotype, was a significantly independent predictor (p = 0.026). Our findings suggest that ALAD genotype may modify the effect of lead on the renal excretion of uric acid as well as overall renal function among middle-aged and elderly men who had community (nonoccupational) exposures to lead. Additional research is needed to ascertain whether this constitutes a true gene-environment interaction and, if so, its clinical impact.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Bone and Bones
- Creatinine
- Cross-Sectional Studies
- Environmental Exposure
- Exons
- Genotype
- Humans
- Kidney
- Kidney Diseases
- Lead
- Male
- Middle Aged
- Polymorphism, Genetic
- Porphobilinogen Synthase
- Regression Analysis
- Uric Acid
- Veterans
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.
MeSH Terms
- Aged
- Aging
- Bone and Bones
- Environmental Exposure
- Genetic Predisposition to Disease
- Genotype
- Humans
- Lead
- Lead Poisoning
- Longitudinal Studies
- Male
- Massachusetts
- Middle Aged
- Patella
- Polymorphism, Genetic
- Porphobilinogen Synthase
- Smoking
- Socioeconomic Factors
- Tibia
- Vitamin D
Prevalence of lead exposure and elevated tissue lead was determined in Laysan albatross (Diomedea immutabilis) in Hawaii. The relationship between lead exposure and proximity to buildings, between elevated blood lead and droopwing status, and elevated liver lead and presence of lead-containing paint chips in the proventriculus in albatross chicks was also examined. Finally, the effects of lead on the enzyme delta-aminolevulinic acid dehydratase (ALAD) was determined. There was a significant association between lead exposure or elevated tissue lead and proximity to buildings in albatross chicks and presence of lead paint chips in the proventriculus and elevated liver lead in carcasses. Although there was a significant association between elevated blood lead and droopwing chicks, there were notable exceptions. Prevalence of elevated tissue lead in albatross chicks was highest on Sand Island Midway and much less so on Kauai and virtually nonexistent in other areas. Prevalence of lead exposure decreased as numbers of buildings to which chicks were exposed on a given island decreased. Laysan albatross adults had minimal to no lead exposure. There was a significant negative correlation between blood lead concentration and ALAD activity in chicks. Based on ALAD activity, 0.03-0.05 microg/ml was the no effect range for blood lead in albatross chicks.
MeSH Terms
- Aging
- Animals
- Bird Diseases
- Birds
- Environmental Exposure
- Hawaii
- Lead
- Lead Poisoning
The activities of the heme biosynthetic enzymes ALA synthase (ALAS) and ALA dehydrase (ALAD) and the heme degradative enzyme heme oxygenase were analyzed from bone marrow cells obtained from young, middle-aged, and senescent rats. There was age-related reduced activity of bone marrow ALAS but no age-related difference in the activity of ALAD. In contrast, heme oxygenase activity was 50% greater in the senescent marrow cells. Incorporation of 14C-glycine into heme was 45% less in senescent rat marrow cells, whereas incorporation of 14C-delta-aminolevulinic acid was not related to age. Senescent bone marrow cells demonstrated a marked reduction in 14C-leucine and 3H-uridine incorporated into protein and nucleic acid synthesis, respectively. In vitro erythroid colony (CFUE) growth by senescent bone marrow cells was as much as 40% less compared with young bone marrow cells. The decreased ability to form CFUE by the senescent bone marrow cells may be related to reduced ALAS activity and increased heme oxygenase activity. Thus, part of the aging process appears to involve fluctuations in the enzyme activities and protein synthesis involved with metabolism of heme.
MeSH Terms
- 5-Aminolevulinate Synthetase
- Aging
- Animals
- Erythrocytes
- Erythropoiesis
- Glycine
- Hematopoietic Stem Cells
- Heme
- Heme Oxygenase (Decyclizing)
- Leucine
- Male
- Porphobilinogen Synthase
- Rats
- Rats, Inbred Strains
- Uridine
From a follow-up study (1976-1985) on lead exposure in population groups living in the vicinity of a lead smeltery, and those from a control area, data were selected on 222 simultaneous measurements of biological indicators of effective lead exposure (absorption) in the blood of children and their mothers. The range of lead exposure levels in both the children and the mothers was very wide (from "normal" to largely excessive lead exposure) as indicated by blood lead (PbB), activity of delta-aminolaevulinic acid dehydratase (ALAD) and erythrocyte zinc-protoporphyrin (ZnPP). A highly significant (P less than 0.001) exponential decrease in ALAD with respect to PbB, as well as an exponential increase in ZnPP with respect to PbB, was found in children and their mothers. Highly significant (P less than 0.001) relationships were found between the levels of PbB, ALAD, and ZnPP in the children with respect to those found in their mothers, indicating the relevant influence of a similar microenvironment (e.g. lead in indoor air and in household dust) and life-style (e.g. household hygiene habits and food preferences) on the level of effective individual lead exposure. Although these relationships have indicated generally higher levels of lead in children with respect to their mothers, the hypothesis of a relatively higher absorption and retention of lead in children of a lower age than that in children of a higher age could not be confirmed, which is in agreement with our previous observations. However, when the three subgroups according to the age of the children were compared (i.e. 0.3-4.5 years, 5-10 years, and 10.5-15 years), it appeared that children aged 0.3-4.5 years had the lowest lead absorption and those aged 5-10 years the highest in relation to their mothers. Within each of these subgroups, a tendency towards relatively higher effective lead exposure in children (i.e. the child/mother ratio of PbB, ALAD and ZnPP levels) with respect to an increase in environmental lead exposure level has been observed.
MeSH Terms
- Adolescent
- Adult
- Aging
- Child
- Child, Preschool
- Environmental Exposure
- Environmental Monitoring
- Hemoglobins
- Humans
- Infant
- Lead
- Middle Aged
- Porphobilinogen Synthase
- Protoporphyrins
Activity of 5-aminolevulinate hydrolyase (delta-aminolevulinic acid dehydrase, ALAD, EC 4.2.1.24) in the blood was determined in relation to age in humans and rats, and the following findings were obtained: (1) In the group which consisted of 47 women (mean age 46, ranged 24 to 62 years) living in a rural district, where the atmospheric lead concentration was 0.5 micron/m3, a significant negative correlation between ALAD activity and age was observed statistically (r = -0.54). However, in the group which consisted of 53 women of similar age group living in an urban district, where the atmospheric lead concentration was 1.9 microng/m3, showed a lower level of the ALAD activity than that of the former group and no correlation was found r = -0.01) between ALAD activity and age. (2) The ALAD activity of intact rats showed a decrease with age. The decrease proceeds rapidly within 8 weeks of age and becomes stable after reaching 25 weeks of age or 300 g of body weight. The value of the activity after 25 weeks of age was about one tenth of that at 5 weeks of age or 100 to 130 g of body weight. (3) Fifteen intact rats weighing 240 to 705 g were divided into three groups according to their body weight and were injected with lead acetate solution equivalent to 1 mg Pb/kg intraperitoneally in order to examine the sensitivity to lead in rats that have variation of ALAD activity by age or by body weight. The ALAD activity of these rats fell to the same level in all groups independently of the activity or the body weight before injection.
MeSH Terms
- Adult
- Aged
- Aging
- Air Pollution
- Animals
- Body Weight
- Female
- Humans
- Hydro-Lyases
- Lead
- Male
- Middle Aged
- Porphobilinogen Synthase
- Rats
A correlation between blood reticulocyte percent and the activity of erythrocytic delta-aminolevulinic acid dehydratase (ALAD) in the developing rat has been established during the progression from a state of macrocytic hypochromic anemia at birth to a normocytic normochromic state at puberty, and finally to a state just prior to adulthood at which the reticulocyte percent had stabilized. Both reticulocyte percent and erythrocytic ALAD activity was found to decrease with age, rapidly at first until a normocytic normochromic state was reached at puberty and then more slowly until just before adulthood when both plateaued. A direct, linear correlation between erythrocytic ALAD activity and blood reticulocyte percent was found with a P value of less than 0.001. These findings should be carefully considered when using the rat as a model for lead poisoning and possibly for other disorders of heme biosynthesis.
MeSH Terms
- Aging
- Animals
- Cell Count
- Erythrocyte Count
- Erythrocytes
- Male
- Porphobilinogen Synthase
- Rats
- Reticulocytes