The interaction of lead exposure and arylsulfatase A genotype affects sulfatide catabolism in human fibroblasts

Lead exposure causes cognitive and behavioral deficits in some affected chi ldren. We propose that a contributing mechanism for the neurological damage is that lead induces critically low levels of arylsulfatase A (ASA) at sen sitive stages of nervous system development. It is hypothesized that the co mbined effects of a single nucleotide polymorphism (SNP) in human ASA which results in reduced levels of the enzyme, and lead concentrations which dec rease ASA activity culminate in cellular enzymic activity that is below a c ritical threshold required for the maintenance of normal nervous system fun ction. Human fibroblasts grown in the presence of 20 mu M lead acetate exhi bit a more than 60% decrease of cellular ASA enzyme protein. Lead treatment of cells from individuals with the SNP(s) of pseudodeficient ASA, but not those from subjects with the normal gene, results in a significant decrease in ability of the cells to desulfate sulfatide, the substrate of ASA. The decrease in the degree of sulfatide catabolism is consistent with possible enhanced lead-induced neurobehavioral effects in individuals homozygous for the pseudodeficiency polymorphism(s) of ASA. (C) 2000 Intox Press, Inc.