Quantitative trait locus analysis of the development of pulmonary tolerance to inhaled zinc oxide.
Wesselkamper-SC; Chen-LC; Kleeberger-SR; Tang-MS; Gordon-T
Am J Respir Crit Care Med 2002 Apr; 165(8)(Suppl):A46
As a result of repeated exposure to inhaled toxic agents in different occupations and environmental settings, individuals may develop tolerance to adverse health effects. Thus, the identification of innate and extrinsic factors that influence the ability to develop tolerance is a significant issue among inbred strains of mice, the BALB/cByJ (CBy) strain exhibits greater pulmonary tolerance to PMN and protein levels in lavage fluid than DBA/2J (D2) following 5 successive exposures (5X) to 10 mg/m3 ZnO. A genome-wide screen using 298 F2 mice (CByD2FlxCByD2FI) that were phenotyped for the development of pulmonary tolerance following 5X ZnO exposure identified a significant quantitative trait locus (QTL) for the BAL protein phenotype on chromosome 1. An excellent candidate gene within this QTL is the toll-like receptor 5 gene (Tlr5) which is part of a family of toll-like receptor genes that are important in the induction of the innate immune response. Affymetrix GeneChip oligonucleotide microarray analyses were conducted to examine ZnO- induced expression of genes up-and downstream in the toll-like receptor signaling pathway and identify candidate genes present in other chromosomal regions of interest. Interestingly, the toll-like receptor 4 gene (Tlr4) has been shown to be a strong candidate susceptibility gene for ozone-induced increases in the BAL protein phenotype in inbred mice. Taken together, these studies suggest that the toll-like receptor pathway may playa role in genetic regulation of the pulmonary response to inhaled particles and gases.
Inhalation-studies; Inhalants; Toxic-materials; Toxins; Environmental-factors; Genetic-factors; Genetics; Genes; Animals; Animal-studies; Pulmonary-system; Pulmonary-function; Immune-system; Laboratory-animals; Zinc-compounds
Abstract; Conference/Symposia Proceedings
Research Tools and Approaches; Exposure Assessment Methods; Disease and Injury; Asthma and Chronic Obstructive Pulmonary Disease; Pulmonary System Disorders; Other Occupational Concerns
American Journal of Respiratory and Critical Care Medicine, 2002 International Conference, The American Thoracic Society, Atlanta, Georgia, May 17-22, 2002