A Murine Model of Genetic Susceptibility to Lead Bioaccumulation

Previous reports have shown that blood lead levels in humansare associated with a polymorphic form of -aminolevulinate dehydratase(ALAD), an enzyme of heme biosynthesis that binds and is inhibitedby lead. We hypothesized that ALAD levels may influence thedistribution and accumulation of lead in the blood and targetorgans. To assess this, we studied strains of mice that differin the numbers of copies of the ALAD gene. Our findings showedthat mice with a duplication of the ALAD gene (DBA) accumulatedtwice the amount of lead in their blood and had higher leadlevels in kidney and liver than mice with a single copy of thegene (C57) exposed to the same oral doses of lead during adulthood.Hybrid animals showed intermediate blood lead levels. Levelsof blood zinc protoporphyrin (ZPP) increased with lead exposurein C57 animals while they were not affected in DBA mice, suggestingprotection from production of this abnormal enzyme in mice witha duplication of the gene. Except for these protective effectsin the formation of ZPP in DBA animals, duplication of the ALADgene was found to increase lead accumulation. We conclude thatalthough these mouse strains do not precisely replicate thepolymorphism observed in humans, they may be used as a modelto study genetic influences in lead bioaccumulation. Understandinggenetic factors that affect susceptibility to lead-induced intoxicationcould have important implications for public health and interventioninitiatives. These mouse strains may represent a useful modelfor future study of the role of ALAD in lead intoxication.