Lead causes human fibroblasts to mis-sort arylsulfatase A.
Toxicology
; 163(2-3): 107-14, 2001 Jun 21.
Article
en En
| MEDLINE
| ID: mdl-11516520
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 reduced levels of the enzyme, and lead concentrations that decrease ARSA activity, culminate in cellular enzymic activity that is below a critical threshold required for the normal nervous system function. Human fibroblasts grown in the presence of lead acetate exhibit a 65% decrease in ARSA protein, resulting in a significant decrease in the ability to catabolize sulfatide in cells from individuals with the SNP(s) of pseudodeficient ARSA, but not those from subjects with the normal gene (Poretz et al., Neurotoxicology 21 (2000) 379). The present study examines the potential of lead to affect the biosynthesis, trafficking and turnover of ARSA in human fibroblasts. Fibroblasts, grown in 20 microM lead, displayed a 44--58% increase in the rate of proliferation. Lead caused a decrease of approximately 33% in the accumulation of newly synthesized intracellular ARSA. This difference was not due to increased rates of intracellular degradation of ARSA or decreased levels of ARSA mRNA. Lead, however, caused the newly synthesized enzyme to be trafficked through the secretion pathway, resulting in decreased amounts of the enzyme 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 directing the enzyme to lysosomes.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Cerebrósido Sulfatasa
/
Fibroblastos
/
Plomo
Tipo de estudio:
Etiology_studies
Límite:
Humans
Idioma:
En
Revista:
Toxicology
Año:
2001
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Irlanda