The long-term goal is to determine the relationship of inherited, deficiencies of lysosomal enzymes and susceptibility to pathologies caused by toxicants. This proposal focuses on lead-induced neurotoxicity. The broad objective of the project is to define a genetic factor which may cause certain individuals to be hypersusceptible to lead-induced neurobehavioral abnormalities allowing for a more detailed dissection of the biochemical processes involved in lead-induced neuropathologies. A consequence of this research may be the identification of individuals in an at risk population who are hypersusceptible to lead toxicity and therefore, may be targeted for preventive treatment. The hypothesis to be tested is that a contributing mechanism for lead-induced neurological damage is that the metal causes reduced levels of arylsulfatase A (ASA) at critical stages of nervous system development. The abnormally reduced levels of ASA is the product of the interaction of a genetic polymorphism in ASA which results in reduced levels of the enzyme, and lead concentrations which cause a further reduction in the cellular activity of ASA. Due to this compound effect, the amount of enzymic activity falls below a critical threshold level needed to maintain normal levels of sulfatide. Individuals with this genetic abnormality of ASA may be predisposed to lead-induced neuropathology. A relatively common polymorphism in the human ASA gene results in greatly reduced cellular levels of the enzyme. The frequency of the homozygous state for this polymorphism is three times greater in the African-American than Caucasian-American population. Furthermore, lead is capable of causing a reduction in cellular ASA enzymic activity in vivo with rodents, and in vitro with human cell cultures. The objectives of this proposal are to examine the effect of lead on the cellular activity of central nervous system ASA and enzymes involved in the biosynthesis of sulfatide, as well as tissue concentrations of glycosphingolipids in new born rats who have been exposed to the metal in utero and subsequently through maternal milk from exposed mothers, and in in vitro cultured rat oligodendrocytes, and on sulfatide catabolism in in vitro cultured fibroblasts from humans who possess ASA genetic polymorphisms, as well as examine the clinical association in children of the pseudodeficient ASA genotype which results in reduced levels of ASA, with both cognitive functions and history of lead exposure.
