δ-Aminolevulinic Acid Dehydratase (ALAD) Polymorphism and Susceptibility of Workers Exposed to Inorganic Lead and Its Effects on Neurobehavioral Functions

doi:10.1016/j.neuro.2004.01.010

NeuroToxicology

Volume 25, Issue 6, December 2004, Pages 1041-1047

https://doi.org/10.1016/j.neuro.2004.01.010 Get rights and content

Abstract

We carried out a cross-sectional study on a group of male workers to determine the frequency of δ-aminolevulinic acid dehydratase (ALAD) polymorphisms among Chinese, Malays and Indians workers who were exposed to low to medium levels of inorganic lead. Also, the association between ALAD1 and ALAD2 genotypes and neurobehavioral functions among these workers were investigated. A total of 120 male workers were studied. Blood and urine were collected for each worker to determine the ALAD genotypes, blood lead levels, ALAD, and urinary δ-aminolevulinic acid (ALAU). ALAD1-1 was the predominant genotype for all three ethnic groups while ALAD2-2 was the rarest. The distribution of ALAD1-2 was higher among Malays (16.7%) and Indians (14.3%), compared to Chinese (3.6%). Selected tests from the World Health Organization Neurobehavioral Core Test Battery (WHO-NCTB) were used. Although workers in the ALAD1-1 and ALAD1-2/2-2 groups had comparable blood lead levels, the 106 workers with ALAD1-1 genotypes have significantly higher urinary ALA and significantly poorer neurobehavioral scores involving motor dexterity compared with those who have ALAD1-2/2-2 genotypes (13 workers). It is postulated that the ALAD2 allele may exert protective measures against the neurotoxic effects of lead. Further study involving a larger cohort of workers with the ALAD2 allele would be needed to confirm this hypothesis.

Section snippets

INTRODUCTION

Exposure to inorganic lead (henceforth referred to as lead) in the environmental and occupational settings continues to be a serious public health problem. At high exposure levels, lead causes encephalopathy, kidney damage, anaemia and toxicity to the reproductive system. Even at lower doses, lead produces alterations in cognitive development in children. A safe level of lead exposure has not been defined, as health risks associated with lead are found at ever-lower doses (Onalaja and Claudio,

METHODS

The design of the study was cross-sectional in nature. The study has been approved by the National University Hospital Ethics Committee. Informed consent was obtained from each worker before the commencement of the study.

RESULTS

Table 1 shows the basic characteristics of the study population. The mean duration of exposure is 10.2 years but with a wide range of 0.1–31 years. Chinese formed a large portion of the subjects while the proportion of Malays and Indians were fairly even. Tests of the blood lead show that this group of subjects is not exposed to high levels of lead. More than 80% of the workers had blood leads which are <30 μg/100 ml. ALAD1-1 is the predominant genotype for all the three ethnic groups while

DISCUSSION

The majority of the Chinese in this study have the ALAD1-1 (96.4%) genotype with only 3.6% having ALAD1-2 and none with ALAD2-2. The frequencies of the Chinese ALAD genotype in this population are fairly similar to that of Chinese in a study conducted in China (ALAD1-1 of 0.92; ALAD1-2 of 0.08; ALAD2-2 of 0) (Shen et al., 2001), and also Taiwanese (ALAD1-1 of 0.955; ALAD1-2 of 0.044; ALAD2-2 of 0.002) and Thai populations (ALAD1-1 of 0.941; ALAD1-2 of 0.058; ALAD2-2 of 0.001) (Kelada et al.,

Acknowledgements

This study was supported from a research Grant no: 01/1/21/19/186 from the Agency for Science, Technology and Research, Biomedical Research Council (BMRC), Singapore.

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Cited by (36)

Delta-aminolevulinic acid dehydratase (ALAD) polymorphism in lead exposed Bangladeshi children and its effect on urinary aminolevulinic acid (ALA)
2015, Environmental Research
Citation Excerpt :
However, except for among Korean and Japanese subjects, little previous research has been undertaken on the subject among Asian populations. The frequency of ALAD 1-2 was much higher among Malay (17.5%) and Indian (15.2%) subjects, compared to Chinese (8.4%) subjects in a study of a small group of occupationally exposed workers (Chia et al., 2004). A relatively high frequency of ALAD 2 was also found in Asian populations in West Asia and Sri Lanka (Fujihara et al., 2009).
Lead has long been recognized as a harmful environmental pollutant. People in developing countries like Bangladesh still have a higher risk of lead exposure. Previous research has suggested that the delta-aminolevulinic acid dehydratase (ALAD) genotype can modify lead toxicity and individual susceptibility. As children are more susceptible to lead-induced toxicity, this study investigated whether the ALAD genotype influenced urinary excretion of delta-aminolevulinic acid (U-ALA) among children exposed to environmental lead in Bangladesh.
Subjects were elementary schoolchildren from a semi-urban industrialized area in Bangladesh. A total of 222 children were studied. Blood and urine were collected to determine ALAD genotypes, blood lead levels and urinary aminolevulinic acid (U-ALA).
The mean BPb level was 9.7 µg/dl for the study children. BPb was significantly positively correlated with hemoglobin (p<0.01). In total, allele frequency for ALAD 1 and 2 was 0.83 and 0.17 respectively. The mean U-ALA concentration was lower in ALAD1-2/2-2 carriers than ALAD1-1 carriers for boys (p=0.001). But for girls, U-ALA did not differ significantly by genotype (p=0.26). When U-ALA was compared by genotype at the same exposure level in a multiple linear regression analysis, boys who were ALAD1-2/2-2 carriers still had a lower level of U-ALA compared to ALAD1-1carriers.
This study provides information about the influence of ALAD polymorphism and its association with U-ALA in Bangladeshi children. Our results indicate that the ALAD1-2/2-2 genotype may have a protective effect in terms of U-ALA for environmentally lead exposed boys.
Reconsideration of the WHO NCTB strategy and test selection
2014, NeuroToxicology
The World Health Organization-recommended neurobehavioral core test battery (NCTB) became the international standard for identifying adverse human behavioral effects due to neurotoxic chemical exposure when it was first proposed in 1983. Since then the WHO NCTB has been repeatedly cited as the basis for test selection in human neurotoxicology research. A discussion group was held before the International Symposium on Neurobehavioral Methods and Effects in Occupational and Environmental Health to review the NCTB and reconsider its tests. The workshop made three consensus recommendations to the International Congress on Occupational Health (ICOH) Scientific Committee on Neurotoxicology and Psychophysiology (SCNP):.
- 1.
  A ‘screening’ battery of broadly sensitive tests is needed as guidance to the field of human neurotoxicology
- 2.
  The SCNP should convene a panel to reconsider the functions measured and the tests in the WHO NCTB
- 3.
  Three disciplines should be represented in the panel recommending a revised NCTB: neuropsychology; experimental psychology; neurology
This recommendation will be pursued at the next meeting of the International Congress on Occupational Health (ICOH) Scientific Committee on Neurotoxicology and Psychophysiology (SCNP).
Chelation Therapy
2013, Comprehensive Inorganic Chemistry II (Second Edition): From Elements to Applications
Chelation therapy is the medical treatment for reducing the toxic effect of metals. Chelating agents are organic compounds that are capable of linking to metal ions to form less toxic species that are easily excreted from the body. Chelators bind metals and remove them from intracellular or extracellular spaces. Hydrophilic chelators are known to enhance urinary metal excretion, but their effects are mainly limited to extracellular metal pools. While lipophilic chelators can decrease intracellular stores, they may redistribute metals to the brain. Prolonged use of chelation therapy is compromised by side effects. The metal selectivity of chelators is important, due to the risk of essential metal depletion. Dimercaptosuccinic acid and dimercaptopropionic sulfonate have presently gained increased acceptance among clinicians, undoubtedly improving the management of metal intoxication. However, development of new safer chelators suited for long-term oral administration for chelation of metal deposits is an important challenge for future research.
Effect of the delta-aminolevulinic acid dehydratase gene polymorphism on renal and neurobehavioral function in workers exposed to lead in China
2010, Science of the Total Environment
Effects of delta-aminolevulinic acid dehydratase (ALAD) polymorphisms on the renal and neurobehavioral functions were investigated in Chinese workers from a storage battery plant exposed to inorganic lead. Blood and urine were collected from each worker to determine the ALAD genotypes, blood lead levels (PbB), urinary β2-MG and urinary NAG activity. The World Health Organization Neurobehavioral Core Test Battery (WHO-NCTB) was used. Of the 135 lead workers tested for ALAD genotype, 126 were ALAD1-1, 9 were ALAD1-2 but none were ALAD2-2. The gene frequencies of ALADl-1 and ALADl-2 were 93.33% and 6.67%, respectively. The workers with ALAD1-2 genotype had significantly higher concentrations of PbB (62.52 µg/dl vs. 41.02 µg/dl), urinary NAG (22.01 U/gCr vs. 13.49 U/gCr), urinary β2-MG (194.98 μg/gCr vs. 112.88 μg/gCr), and digit span backward (DSB) score (6.67 vs. 5.33) than those of ALAD1-1 genotype. Urinary NAG of ALAD1-2 genotype carriers was significantly higher than that of ALAD1-1 genotype under the same blood lead level (b_i 0.75 vs. b_i 0.29). Interaction between PbB and ALAD genotypes has a significant influence on NAG (P = 0.02) and β₂-MG (P = 0.01). It is postulated that the workers with the ALAD2 allele appear to be more susceptible to the effects of lead on renal injury, whereas neurobehavioral functions in ALAD1 homozygote tend to be more vulnerable.
Ethnic variation in genotype frequencies of δ-aminolevulinic acid dehydratase (ALAD)
2009, Toxicology Letters
Citation Excerpt :
This enzyme has a function to catalyze the condensation of two molecules of δ-aminolevulinic acid (ALA) to form monopyrole porphobilinogen, which is the precursor of hemes, as well as chlorophyll, cytochromes, and cobalamines. Zinc is essential for ALAD enzymatic activity, while lead strongly inhibited the activity through the displacement of zinc at the metal binding site (Warren et al., 1998), resulting in the accumulation of ALA, which has neurotoxic and genotoxic effects (Brennan and Cantrill, 1979; Warren et al., 1998; Kamel et al., 2003; Chia et al., 2004). Several studies in humans have reported that ALAD activity decreased with lead exposure (Sakai and Morita, 1996; Sakai, 2000), demonstrating that ALAD activity is one of the most sensitive indicators of lead poisoning.
δ-Aminolevulinic acid dehydratase (ALAD) is a cytosolic enzyme in the heme biosynthetic pathway. The ALAD is controlled by two codominant alleles (ALAD1 and ALAD2), which result in a Asn-Lys substitution at amino acid position 59 of the mature enzyme based on a single nucleotide polymorphism (SNP) (G177C) leading three phenotypes (ALAD1-1, ALAD1-2, and ALAD2-2). Previous studies have shown that this polymorphism is related to lead toxicity. There is little evidence showing interethnic differences in the distribution of this polymorphism. We examined the distribution of genetic variants of the ALAD G177C polymorphism in four Asians, three Africans, and three Mexicans. Genomic DNA was extracted from blood or bloodstain, and the genotypes for the ALAD polymorphism were determined by PCR followed by RFLP digestion and gel electrophoresis. We found a notable interethnic disparity in the distribution of ALAD G177C genotypes and alleles. The frequencies of ALAD2 in Asian populations were comparable to those in Caucasians, while Africans had no mutation allele. These findings may help us understand the interethnic disparities in susceptibility to lead toxicity.
Lead and cognitive function in ALAD genotypes in the third National Health and Nutrition Examination Survey
2009, Neurotoxicology and Teratology
Citation Excerpt :
Reaction time decreased as the blood lead concentration increased from 0 to 30 µg/dl and increased thereafter. Chia et al. [11] studied workers that produced lead stabilizers and found that men with the CC/CG genotype performed the grooved peg board test more rapidly than men with the GG genotype. This test requires putting 25 key-shaped pegs into holes as quickly as possible.
The relationship between the blood lead concentration and cognitive function in children and adults with different ALAD genotypes who participated in the third National Health and Nutrition Examination Survey was investigated. The relationship between blood lead and serum homocysteine concentrations was also investigated. In children 12 to 16 years old, no difference in the relationship between cognitive function and blood lead concentration between genotypes was found. In adults 20 to 59 years old, mean reaction time decreased as the blood lead concentration increased in the ALAD rs1800435 CC/CG group. This represents an improvement in performance. In adults 60 years and older, no difference in the relationship between cognitive function and blood lead concentration between genotypes was found. The serum homocysteine concentration increased as the blood lead concentration increased in adults 20 to 59 years old and 60 years and older, but there were no differences between genotypes. The mean blood lead concentration of children with the ALAD rs1800435 CC/CG genotype was less than that of children with the GG genotype.

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^☆: A Letter to the Editor written by the Authors above citing this research has been published in Occupational and Environmental Medicine, 2004; 61(8): 720.

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δ-Aminolevulinic Acid Dehydratase (ALAD) Polymorphism and Susceptibility of Workers Exposed to Inorganic Lead and Its Effects on Neurobehavioral Functions☆

Abstract

Section snippets

INTRODUCTION

METHODS

RESULTS

DISCUSSION

Acknowledgements

Environ. Res.

Attentional correlates of dentin and bone lead levels in adolescents

Arch. Environ. Health

Lead binding to delta-aminolevulinic acid dehydratase (ALAD) in human erythrocytes

Pharmacol. Toxicol.

Cumulative blood lead levels and neurobehavioral test performance

NeuroToxicology

Neurobehavioural testing in workers occupationally exposed to lead: systematic review and meta-analysis of publications

Occup. Environ. Med.

Motor performance after unilateral hemisphere damage in patients with tumor

Arch. Neurol.

Association between aminolevulinate dehydrogenase genotype and blood lead levels in Taiwan

J. Occup. Environ. Med.

δ-Aminolevulinic acid dehydratase genotype and lead toxicity: a HuGE review

Am. J. Epidemiol.