Lead causes human fibroblasts to mis-sort arylsulfatase A

Lead exposure causes cognitive and behavioral deficits in some children. We have proposed that the effects of single nucleotide polymorphisms (SNP) of the human pseudodeficient arylsulfatase A (ARSA) gene that result in reduc ed levels of the enzyme, and lead concentrations that decrease ARSA activit y, culminate in cellular enzymic activity that is below a critical threshol d required for the normal nervous system function. Human fibroblasts grown in the presence of lead acetate exhibit a 65% decrease in ARSA protein, res ulting in a significant decrease in the ability to catabolize sulfatide in cells from individuals with the SNP(s) of pseudodeficient ARSA, but not tho se from subjects with the normal gene (Poretz et al., Neurotoxicology 21 (2 000) 379). The present study examines the potential of lead to affect the b iosynthesis, trafficking and turnover of ARSA in human fibroblasts. Fibrobl asts, grown in 20 muM lead. displayed a 44-58% increase in the rate of prol iferation. Lead caused a decrease of approximately 33% in the accumulation of newly synthesized intracellular ARSA. This difference was not due to inc reased rates of intracellular degradation of ARSA or decreased levels of AR SA mRNA. Lead, however, caused the newly synthesized enzyme to be trafficke d through the secretion pathway, resulting in decreased amounts of the enzy me in intracellular compartments. Though lead exposure results in increased cellular proliferation, it appears to cause decreased intracellular steady -state levels of ARSA by affecting the sorting cues and/or mechanisms direc ting the enzyme to lysosomes. (C) 2001 Elsevier Science Ireland Ltd. All ri ghts reserved.