| As a result of repeated exposures to inhaled toxicants such as zinc oxide (ZnO), numerous individuals acquire tolerance and display reduced symptoms. Pulmonary tolerance can be characterized as the lung's ability to withstand the adverse actions of a toxic compound following repeated exposures. To ascertain whether tolerance is developed in an animal model, outbred NIH-Swiss mice were exposed to 1.0 mg/m3 ZnO for 1, 3, or 5 days (1X, 3X, or 5X), and polymorphonuclear leukocyte (PMN) and protein levels in bronchoalveolar lavage fluid (BALF) were measured. These mice acquired tolerance to PMN infiltration into the lungs, as total PMNs returned near baseline in 5X-exposed animals as compared to 1X-exposed mice. Development of tolerance to changes in lavageable protein, however, was not observed. Based on this outbred mouse model, eleven inbred mouse strains were exposed 1X or 5X to 1.0 mg/m3 ZnO to determine whether genetic background is important to the development of pulmonary tolerance to inhaled toxicants. Significant interstrain variation in PMN and protein responses was observed between 1X and 5X exposures, which is indicative that genetic background has an important role in the development of pulmonary tolerance. The BALB/cByJ (CBy) strain and the DBA/2J (D2) strain were the most tolerant and non-tolerant, respectively, and the CByD2F1/J offspring were non-tolerant. To investigate candidate genes that may be involved in the molecular mechanism(s) regulating the development of pulmonary tolerance, a genome-wide screen using CByD2F2 intercross mice phenotyped for protein, PMNs, and macrophage in BALF after 5X ZnO exposure identified the following quantitative trait loci (QTLs): a significant QTL on chromosome 1 and suggestive QTLs on chromosomes 4 and 5 for the protein phenotype, and suggestive QTLs on chromosomes 1 and 5 for the PMN and macrophage phenotypes, respectively. Within the significant protein QTL on chromosome 1, the toll-like receptor 5 gene (Tlr5) was identified as a putative gene candidate. The development of tolerance to protein in BALF in Tlr5-mutant MOLF/Ei mice after 1X and 5X ZnO exposure suggests that the toll-like receptor pathway may play a role in genetic regulation of the pulmonary response from repeated exposure to inhaled toxicants. |
