A murine model of genetic susceptibility to lead bioaccumulation.
Previous reports have shown that blood lead levels in humans are associated with a polymorphic form of delta-aminolevulinate dehydratase (ALAD), an enzyme of heme biosynthesis that binds and is inhibited by lead. We hypothesized that ALAD levels may influence the distribution and accumulation of lead in the blood and target organs. To assess this, we studied strains of mice that differ in the numbers of copies of the ALAD gene. Our findings showed that mice with a duplication of the ALAD gene (DBA) accumulated twice the amount of lead in their blood and had higher lead levels in kidney and liver than mice with a single copy of the gene (C57) exposed to the same oral doses of lead during adulthood. Hybrid animals showed intermediate blood lead levels. Levels of blood zinc protoporphyrin (ZPP) increased with lead exposure in C57 animals while they were not affected in DBA mice, suggesting protection from production of this abnormal enzyme in mice with a duplication of the gene. Except for these protective effects in the formation of ZPP in DBA animals, duplication of the ALAD gene was found to increase lead accumulation. We conclude that although these mouse strains do not precisely replicate the polymorphism observed in humans, they may be used as a model to study genetic influences in lead bioaccumulation. Understanding genetic factors that affect susceptibility to lead-induced intoxication could have important implications for public health and intervention initiatives. These mouse strains may represent a useful model for future study of the role of ALAD in lead intoxication.
Claudio
L
L
Division of Environmental and Occupational Medicine, Mount Sinai Medical Center, New York, New York 10029-6574, USA.
Lee
T
T
Wolff
M S
MS
Wetmur
J G
JG
D000284:Administration, Oral; D000818:Animals; D002678:Chimera; D004195:Disease Models, Animal; D005260:Female; D007854:Lead / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D007855:Lead Poisoning / Q000209:etiology / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000623:Porphobilinogen Synthase / Q000235:genetics / Q000378:metabolism; D011524:Protoporphyrins / Q000097:blood; D013045:Species Specificity; D014018:Tissue Distribution
D009942:Organometallic Compounds; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D007854:Lead; D000623:Porphobilinogen Synthase; C008261:lead acetate