Article Text

Download PDFPDF

Can δ-aminolevulinic acid dehydratase 2 allele exert certain protective measures against the neurotoxic effects of lead?
  1. S-E Chia,
  2. E Yap,
  3. K-S Chia
  1. Department of Community, Occupational & Family Medicine (MD3), Faculty of Medicine, National University of Singapore, 16, Medical Drive, Singapore 117597, Republic of Singapore;

    Statistics from

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Recently, there has been a lot of interest regarding δ-aminolevulinic acid dehydratase (ALAD) polymorphism and health effects of inorganic lead. Most of these reports focused on renal effects.1,2 There have been reports on the effects of lead on neurobehavioural function among exposed workers.3,4 As far as we know, only one paper has reported the effects of ALAD polymorphism and neurobehavioural testing. Bellinger et al studied 72 adolescents with high (>24 µg/g) and low (<8.7 µg/g) dentin lead levels. The results suggested that the body burden and effects of lead on neurobehavioural functions were worse among ALAD1 homozygotes.5

    We have carried out a cross-sectional study in 106 male workers exposed to low or moderate levels of inorganic lead in order to investigate the association between ALAD1 and ALAD2 genotypes and neurobehavioural functions. Blood and urine were collected for each worker to determine the ALAD genotype, blood lead levels, ALAD, and urinary δ-aminolevulinic acid (ALAU). ALAD1-1 was the predominant genotype for all three ethnic groups (Chinese, Malays, and Indians) while ALAD2-2 was the rarest. The distribution of ALAD1-2 was higher among the Malays (17.5%) and Indians (15.2%) compared to the Chinese (8.4%). A battery of tests from the World Health Organisation Neurobehavioural Core Test Battery and the Grooved Peg Board (GPP) test (an additional test for motor dexterity) were used to assess the neurobehavioural functions.6

    Workers with ALAD1-1 genotype had significantly higher mean ALAU (0.86 mg/g creatinine) compared to workers with ALAD1-2/2-2 genotypes (0.61 mg/g creatinine), even after correcting for possible confounders. No significant differences were noted for mean blood lead and haemoglobin levels for both the groups. ALAD1-2/2-2 genotype workers had significantly better results compared to ALAD1 genotypes in the mean GPP preferred hand (55.5 seconds v 62.6 seconds; p < 0.01), GPP non-preferred hand (60.3 seconds v 67.7 seconds; p < 0.05), and mean GPP scores for preferred and non-preferred hands (57.9 seconds v 65.4 seconds; p < 0.001) tests.

    These two groups of workers had similar lead exposure as measured by their blood lead levels (ALAD1-1 v ALAD1-2/2-2; 21.3 μg/dl v 22.7 μg/dl, respectively). Although there were no significant differences between the mean blood lead levels for the two groups, workers with ALAD1-1 genotypes had significantly higher ALAU compared to those with ALAD1-2/2-2 genotypes. It could be that, given the same amount of lead exposure, ALAD2 alleles are more resilient to the effects of lead as reflected in a lower concentration of ALAU.

    Several lines of evidence have suggested that δ-aminolevulinic acid (ALA) is the neuropathological agent in lead poisoning. In vitro studies have shown the neurotoxicity of ALA. Clinical manifestations of lead poisoning closely resemble those of the acute neurological attacks in the hepatic porphyrias, during which the levels of ALA and porphobilinogen are significantly increased. The role of ALA accumulation in lead poisoning is supported by the report that asymptomatic heterozygotes for the ALAD deficient porphyria are prone to acute lead poisoning when exposed to low levels of lead. Lead is known to inhibit ALAD which results in the build up of ALA, detectable in the plasma and urine at blood lead levels less than 10 µg/dl. Aminolevulinic acid resembles γ-aminobutyric acid receptors in the nervous system; this is thought to be one of the primary mechanisms of lead induced neurotoxicity.1

    Bellinger et al studied 79 subjects (aged 19 or 20 years) using a battery of neuropsychological tests. Sixty seven of the subjects had ALAD1-1 phenotypes, while five had ALAD1-2. On “nearly every endpoint” of the neuropsychological test, the five individuals with the ALAD2 phenotype had better scores compared to 67 subjects with ALAD1, even after adjustment for dentin lead levels.5 Our subjects with ALAD1-2/ALAD-2 genotypes also did significantly better in one of the neurobehavioural tests compared to subjects with ALAD1-1 genotype.

    In summary, workers with ALAD1-1 genotypes have significantly higher ALAU and had significantly poorer neurobehavioural scores involving motor dexterity (GPP) compared with workers with ALAD1-2/2-2 genotypes. The ALAD2 allele may exert certain protective measures against the neurotoxic effects of lead as shown by lower ALAU levels among workers with the ALAD2 allele. This hypothesis is preliminary given the small sample size of the group with ALAD1-2/2-2 genotypes. Further study involving a larger cohort of workers with ALAD2 allele would be needed to confirm this.