Am. J. Respir. Cell Mol. Biol., Volume 22, Number 5, May, 2000 574-581

Genetic Linkage Analysis of Susceptibility to Particle Exposure in Mice

Yoshinori Ohtsuka, Kiana J. Brunson, Anne E. Jedlicka, Wayne Mitzner, Robert W. Clarke, Liu-Yi Zhang, Scott M. Eleff, and Steven R. Kleeberger

Departments of Environmental Health Sciences and Anesthesiology/Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland

Particle-induced increases in respiratory morbidity and mortality have been observed worldwide in industrialized cities but the toxicologic mechanisms have not been elucidated. It is hypothesized that subpopulations including the elderly and individuals with cardiopulmonary disease are particularly at risk to the effects of exposure. Genetic background is another important host factor that may contribute to interindividual responsivity to particulate exposure. This study was designed to identify susceptibility loci for alveolar macrophage (AM) immune dysfunction induced by inhalation of sulfate-associated carbon particles in susceptible C57BL/6J and resistant C3H/ HeJ inbred mice. AMs were chosen for study because they represent an important component of host defense, and compromised host defense has been hypothesized to be an important factor in particle-induced respiratory morbidity. The quantitative phenotype for these studies was Fc receptor-mediated phagocytic function, an index of AM integrity. Analyses of macrophage dysfunction phenotypes of segregant and nonsegregant populations derived from these two strains indicate that two unlinked genes control susceptibility. A genome-wide linkage analysis of an intercross (F₂) cohort identified significant and suggestive quantitative trait loci (QTLs) on chromosomes 17 and 11, respectively. Candidate susceptibility genes were identified for mice and humans by comparative mapping. Importantly, both QTLs overlap previously identified QTLs for susceptibility to another common pollutant, ozone. This is the first demonstration that genetic background is an important determinant of responsiveness to particle-induced immune dysfunction, and it has important implications for understanding the epidemiologic associations between particulates and morbidity and mortality.

This article has been cited by other articles:

				I A Yang, K M Fong, P V Zimmerman, S T Holgate, and J W Holloway Genetic susceptibility to the respiratory effects of air pollution Thorax, June 1, 2008; 63(6): 555 - 563. [Abstract] [Full Text] [PDF]

				D. M. Brass, J. Tomfohr, I. V. Yang, and D. A. Schwartz Using Mouse Genomics to Understand Idiopathic Interstitial Fibrosis Proceedings of the ATS, January 1, 2007; 4(1): 92 - 100. [Abstract] [Full Text] [PDF]

				Y. Ohtsuka, X-T. Wang, J. Saito, T. Ishida, and M. Munakata Genetic linkage analysis of pulmonary fibrotic response to silica in mice Eur. Respir. J., November 1, 2006; 28(5): 1013 - 1019. [Abstract] [Full Text] [PDF]

				X. Zhang and P. J. Lee Response to Comment on "Cutting Edge: TLR4 Deficiency Confers Susceptibility to Lethal Oxidant Lung Injury" J. Immunol., April 1, 2006; 176(7): 3857 - 3857. [Full Text] [PDF]

				H.-Y. Cho, A. E. Jedlicka, R. Clarke, and S. R. Kleeberger Role of Toll-like receptor-4 in genetic susceptibility to lung injury induced by residual oil fly ash Physiol Genomics, June 16, 2005; 22(1): 108 - 117. [Abstract] [Full Text] [PDF]

				M. Du, R. A. Irani, D. N. Stivers, S.-J. Lee, and E. L. Travis H2-Ea Deficiency Is a Risk Factor for Bleomycin-Induced Lung Fibrosis in Mice Cancer Res., October 1, 2004; 64(19): 6835 - 6839. [Abstract] [Full Text] [PDF]

				A. K. Bauer, A. M. Malkinson, and S. R. Kleeberger Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities Am J Physiol Lung Cell Mol Physiol, October 1, 2004; 287(4): L685 - L703. [Abstract] [Full Text] [PDF]

				S.R. Kleeberger Genetic aspects of susceptibility to air pollution Eur. Respir. J., May 1, 2003; 21(40_suppl): 52S - 56s. [Abstract] [Full Text] [PDF]

				C. K. Haston, M. Wang, R. E. Dejournett, X. Zhou, D. Ni, X. Gu, T. M. King, M. M. Weil, R. A. Newman, C. I. Amos, et al. Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice Hum. Mol. Genet., August 1, 2002; 11(16): 1855 - 1863. [Abstract] [Full Text] [PDF]

				C. K. Haston, X. Zhou, L. Gumbiner-Russo, R. Irani, R. Dejournett, X. Gu, M. Weil, C. I. Amos, and E. L. Travis Universal and Radiation-specific Loci Influence Murine Susceptibility to Radiation-induced Pulmonary Fibrosis Cancer Res., July 1, 2002; 62(13): 3782 - 3788. [Abstract] [Full Text] [PDF]

				A. M. Malkinson, R. A. Radcliffe, and A. K. Bauer Quantitative trait locus mapping of susceptibilities to butylated hydroxytoluene-induced lung tumor promotion and pulmonary inflammation in CXB mice Carcinogenesis, March 1, 2002; 23(3): 411 - 417. [Abstract] [Full Text] [PDF]

				C. G. Tankersley, R. Irizarry, S. Flanders, and R. Rabold Functional Genomics of Sleep and Circadian Rhythm: Selected Contribution: Circadian rhythm variation in activity, body temperature, and heart rate between C3H/HeJ and C57BL/6J inbred strains J Appl Physiol, February 1, 2002; 92(2): 870 - 877. [Abstract] [Full Text] [PDF]

				B. Granum and M. Lovik The Effect of Particles on Allergic Immune Responses Toxicol. Sci., January 1, 2002; 65(1): 7 - 17. [Full Text] [PDF]

				H.-Y. Cho, A. E. Jedlicka, S. P. M. Reddy, L.-Y. Zhang, T. W. Kensler, and S. R. Kleeberger Linkage Analysis of Susceptibility to Hyperoxia . Nrf2 Is a Candidate Gene Am. J. Respir. Cell Mol. Biol., January 1, 2002; 26(1): 42 - 51. [Abstract] [Full Text] [PDF]

				S. C. Wesselkamper, L. C. Chen, S. R. Kleeberger, and T. Gordon Genetic variability in the development of pulmonary tolerance to inhaled pollutants in inbred mice Am J Physiol Lung Cell Mol Physiol, November 1, 2001; 281(5): L1200 - L1209. [Abstract] [Full Text] [PDF]