Genetic susceptibility to lead poisoning.

Abstract

Major strides have been taken in the regulation of lead intoxication in the general population, but studies using genetic markers of susceptibility to environmental toxicants raise the question of whether genes can make certain individuals more vulnerable to environmental toxins such as lead. At least three polymorphic genes have been identified that potentially can influence the bioaccumulation and toxicokinetics of lead in humans. The first gene to be discussed in this review is the gene coding for delta-aminolevulinic acid dehydratase (ALAD), an enzyme of heme biosynthesis, that exists in two polymorphic forms. The resulting isozymes have been shown to affect the blood and bone lead levels in human populations. The effects of ALAD in lead intoxication have also been studied in laboratory mice that differ in the genetic dose for this enzyme. The second gene reviewed here is the vitamin D receptor (VDR) gene. The VDR is involved in calcium absorption through the gut and into calcium-rich tissues such as bone. Recent findings suggest that VDR polymorphism may influence the accumulation of lead in bone. Finally, the third gene to be discussed here that may influence the absorption of lead is the hemochromatosis gene coding for the HFE protein. The presence of mutations in the HFE gene leads to hemochromatosis in homozygotic individuals. Because of the associations between iron and lead transport, it is possible that polymorphisms in the HFE gene may also influence the absorption of lead, but this has not yet been studied. More studies will be needed to define the role of these genes in lead intoxication.ImagesFigure 2Figure 4

Individual susceptibility and genotoxicity in workers exposed to hazardous materials like lead

“…A polymorphism at position 177 leading to a G → C transversion results in occurrence of two alleles (ALAD-1 and ALAD-2) and three isozyme phenotypes, ALAD 1-1, ALAD 1-2, and ALAD 2-2. Studies have suggested that carriers of the ALAD-2 allele have higher blood lead levels (BLL) than ALAD-1 subjects and thus are more susceptible to lead toxicity [14][15][16]. 0304 Some authors suggest that the enhanced capacity of ALAD-2 to bind lead may confer resistance to its harmful effects because subjects with ALAD-2 may have less bio-available lead [15,17].…”

Pyruvate Kinase Activity and δ-Aminolevulinic Acid Dehydratase Activity as Biomarkers of Toxicity in Workers Exposed to Lead

“…One of the most studied genes that can affect the toxicity of Pb codes for d-aminolevulinic acid dehydratase (d-ALAD). d-ALAD is the second enzyme in the heme biosynthetic pathway and plays a role in the pathogenesis of Pb poisoning (Onalaja and Claudio 2000). When d-ALAD activity is deficient due to Pb poisoning, erythrocyte synthesis is inhibited, and blood hemoglobin concentrations decrease.…”

Maternal hemochromatosis gene H63D single-nucleotide polymorphism and lead levels of placental tissue, maternal and umbilical cord blood

“…In a study, in which knockout mice that lack the gene for HFE were used, an increase in transferrin saturation and iron storage in hepatocytes was observed (Waheed et al, 1999). In another study using HFE gene knockout mice, the expression of DMT-1 protein in the duodenum was found to be increased (Cantonwine et al, 2010;Onalaja and Claudio, 2000). The up-regulation of DMT-1 results in the increased absorption of iron and DMT-1 has affinity for several divalent cations such as lead and cadmium.…”