(Epi) Genetic Effects of δ-Aminolevulinic Acid Dehydratase (ALAD) in Children Exposed to Environmental Lead - a primary study from Kabwe, Zambia

Abstract

The δ-aminolevulinic acid dehydratase (ALAD) is a polymorphic enzyme that catalyzes the second step of heme synthesis and has a high affinity for the metal lead (Pb). Previous studies link the methylation and polymorphism of the ALAD gene with negative impacts on lead-exposed people. Kabwe town had a long history of uncontrolled Pb-Zn mining that operated for almost a century and has poisoned generations of children. To date, no data exist regarding the influence of lead exposure on gene polymorphism and DNA methylation level in children from Kabwe. In this study, we conducted a case-controlled study to determine the influence of ALAD G177C genotypes and CpG methylation status in 140 children, aged 2 to 10 years old, exposed to lead.

The mean BLL (± SD) was 19.4 ± 10.6 μg/dL. All the children near the mine dumpsite had BLLs that exceeded the CDC guideline value that raises health concerns; 5 μg/dL. All children were homozygous for the ALAD 1 allele, indicating bioavailable lead in the children’s blood. The methylation frequencies of ALAD CpG and their associations with the risk of lead poisoning showed a significant difference between the areas. The methylated ALAD gene was associated with an increased risk of Pb poisoning (OR = 7.84, p < 0.001) compared with the unmethylated status. In conclusion, lead exposure increases the ALAD methylation, which might be involved in the mechanism of lead toxicity. Moreover, the bioavailable lead, due to the ALAD 1 homozygotes, can transit to soft tissues and the brain. Further larger population-based studies are warranted.