δ-Aminolevulinic acid dehydratase genotype predicts toxic effects of lead on workers' peripheral nervous system.

There is a wide variation in sensitivity to lead (Pb) exposure, which may be due to genetic susceptibility towards Pb. We investigated whether a polymorphism (rs1800435) in the δ-aminolevulinic acid dehydratase (ALAD) gene affected the toxicokinetics and toxicodynamics of Pb. Among 461 Chinese Pb-exposed storage battery and 175 unexposed workers, allele frequencies for the ALAD1 and ALAD2 alleles were 0.968 and 0.032, respectively. The Pb-exposed workers had a higher fraction of the ALAD1-2/2-2 genotype than unexposed workers (7.8% vs. 2.3%, p=0.01). The Pb levels in blood (B-Pb) and urine (U-Pb) were higher in Pb-exposed workers carrying the ALAD2 allele compared to homozygotes for ALAD1 (median B-Pb: 606 vs. 499 µg/L; U-Pb: 233 vs. 164 µg/g creatinine), while there was no statistically significant difference in the unexposed controls (median: 24 vs. 37 µg/L, and 3.9 vs. 6.4µg/g creatinine, respectively). High B-Pb and U-Pb were associated with statistically significantly lower sensory and motor conduction velocities in the median, ulnar and peroneal nerves. At the same B-Pb and U-Pb, ALAD1 homozygotes had lower conduction velocities than the ALAD2 carriers. There were similar trends for toxic effects on haem synthesis (zinc protoporphyrin and haemoglobin in blood) and renal function (albumin and N-acetyl-d-ß-acetylglucosaminidase in urine), but without statistical significance. There was no difference in Pb toxicokinetics and toxicodynamics associated with VDR BsmI polymorphism. Our results show that the ALAD genotype modifies the relationship between Pb and its toxic effects on the peripheral nervous system. This must be considered in the assessment of risks at Pb exposure.

Effect of the delta-aminolevulinic acid dehydratase gene polymorphism on renal and neurobehavioral function in workers exposed to lead in China.

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 beta2-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 (62.52microg/dl vs. 41.02microg/dl), urinary NAG (22.01U/gCr vs. 13.49U/gCr), urinary beta2-MG (194.98microg/gCr vs. 112.88microg/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 beta(2)-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.

p16 promoter methylation in Pb2+ -exposed individuals.

BACKGROUND: One of the principle symptoms of lead poisoning is the development of neurological disorders. Neuronal response is closely related to DNA methylation changes. Aim. In this study, we estimated p16 methylation in nine individuals exposed to lead using methylation-specific polymerase chain reaction followed by analysis of the methylated cytosine content of the product by thermal denaturation. RESULTS: We found that, based on lead blood concentration, lead-exposed individuals were divided into two groups. Among highly exposed individuals (blood Pb(2+) concentration = 51-100 microg/dL), we observed complete CpG methylation, whereas for low Pb(2+) concentrations (blood Pb(2+) concentration = 6-11 microg/dL), we observed partial methylation. CONCLUSION: Our results show that among lead-overexposed individuals, p16 methylation is frequent and extensive, and suggest that DNA methylation could be involved in the mechanism by which lead induces neurotoxicity.

Possibilities of newer ALAD polymorphism influencing human susceptibility to effects of inorganic lead on the neurobehavioral functions.

OBJECTIVE: A cross-sectional study was conducted to study the association between some new ALAD polymorphism and susceptibility to effects of inorganic lead on the neurobehavioral functions. METHOD: We recruited 120 healthy male workers with lead exposure in a factory which manufacture lead stabilizer. The ALAD SNPs studied were HpyCH4, HpyIV RFLP in intron 6, Rsa and Msp RFLP in exon 4, Sau3A in intron 12 and Rsa39488 in exon 5. The World Health Organization Neurobehavioral Core Test Battery (WHO-NCTB) and a few other tests were used. General linear model (GLM) was applied to compare outcome scores between subgroups of each ALAD SNP while controlling for possible confounders. RESULTS: The mean age of the workers was 39.7 years (S.D. 10.7), mean exposure duration of 10.2 years (S.D. 7.9) and mean blood lead of 22.1 microg/dl (S.D. 9.4). Among the 6 SNPs studied, Rsa and Rsa39488 appear to be the main candidate SNPs. Workers with Rsa and Rsa39488 ALAD 2-2 genotypes fare significantly better in the Aiming Pursue Test Correct (AC), Groove Peg Board non-preferred hand (GPNP), Groove Peg Board Mean (GPM), San Ana Preferred Hand (SAP), San Ana Both Hands (SAB) and AC, GPNH, GPM, Digit Symbol (DIS) tests; respectively compared to Rsa and Rsa39488 ALAD 1-1/1-2 genotypes adjusted for age, race, exposure duration and blood lead levels. CONCLUSION: The presence of the homozygote Rsa and Rsa39488 ALAD 2-2 seems to offer some protection against the effect of lead on motor dexterity function. While it may appear that newer ALAD polymorphism other than the commonly reported Msp SNP might influence human susceptibility to effects of inorganic lead on the neurobehavioral functions further study involving a larger cohort of workers with Rsa and Rsa39488 ALAD2 allele would be needed to confirm this inference.

Actualización en marcadores biológicos del saturnismo / Biologic markers of lead poisoning: an update

En el presente artículo pretendemos dar una información útil para la práctica diaria del médico del Trabajo responsable de una población expuesta al plomo. Describimos los marcadores biológicos, sus niveles de referencia y las acciones preventivas a desarrollar en cada caso (AU)

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