title: The interaction of lead exposure and arylsulfatase A genotype affects sulfatide catabolism in human fibroblasts.
abstract: Lead exposure causes cognitive and behavioral deficits in some affected children. We propose that a contributing mechanism for the neurological damage is that lead induces critically low levels of arylsulfatase A (ASA) at sensitive stages of nervous system development. It is hypothesized that the combined effects of a single nucleotide polymorphism (SNP) in human ASA which results in reduced levels of the enzyme, and lead concentrations which decrease ASA activity culminate in cellular enzymic activity that is below a critical threshold required for the maintenance of normal nervous system function. Human fibroblasts grown in the presence of 20 microM lead acetate exhibit 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.
authors.affiliation: Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, NJ 08901-8525, USA. poretz@rci.rutgers.edu
authors.forename: R D
authors.initials: RD
authors.lastname: Poretz
authors.forename: A
authors.initials: A
authors.lastname: Yang
authors.forename: W
authors.initials: W
authors.lastname: Deng
authors.forename: P
authors.initials: P
authors.lastname: Manowitz
mesh_terms: D002478:Cells, Cultured; D002553:Cerebroside-Sulfatase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D009942:Organometallic Compounds / Q000494:pharmacology*; D013433:Sulfoglycosphingolipids / Q000378:metabolism*
chemical_list: D009942:Organometallic Compounds; D013433:Sulfoglycosphingolipids; D002553:Cerebroside-Sulfatase; C008261:lead acetate