Quantitative trait locus mapping of susceptibilities to butylated hydroxytoluene-induced lung tumor promotion and pulmonary inflammation in CXB mice.
We have reported previously [Bauer,A.K. et al. (2001) Exp. Lung Res., 27, 197-216] that the 13 CXB recombinant inbred mouse strains derived from BALB/cByJ and C57BL/6J progenitors vary in their responsiveness to both lung tumor promotion and pulmonary inflammation induced by chronic administration of butylated hydroxytoluene (BHT). Herein we have applied these data, along with markers known to be polymorphic among these strains, to conduct linkage analysis of these susceptibilities. This enabled us to assign provisional quantitative trait loci (QTL) that govern these strain variations in susceptibility as a genetic approach to assessing the influence of inflammation on tumorigenesis. A Chr 15 (39.1-55.6 cM) QTL regulated susceptibility to two-stage carcinogenesis, a protocol in which chronic BHT exposure followed a single urethane injection; a similar QTL on Chr 15 (46.7-61.7 cM) influenced BHT induction of cyclooxygenase-2 (COX-2) expression. A Chr 18 (37-41 cM) QTL modulated both the number of lung tumors induced by 3-methylcholanthrene (MCA) injection with subsequent treatment with BHT as well as BHT-induced ingress of macrophages into airways. Other chromosomal sites that affected either the degree of BHT-elicited macrophage infiltration, Chr 9 (48-61 cM), or COX-2 induction, Chr 10 (59-65 cM), were reported to influence susceptibility to lung tumorigenesis in other strains. The fact that common chromosomal locations regulate both inflammation and carcinogenesis suggests a pathogenic role of inflammatory mediators in tumor development that may be exploited for chemoprevention of lung cancer.
Malkinson
Alvin M
AM
Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA. al.malkinson@uchsc.edu
Radcliffe
Richard A
RA
Bauer
Alison K
AK
D000818:Animals; D002084:Butylated Hydroxytoluene / Q000494:pharmacology*; D002874:Chromosome Mapping / Q000379:methods*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D008126:Lod Score; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D011014:Pneumonia / Q000139:chemically induced* / Q000235:genetics*; D019655:Quantitative Trait, Heritable
D005819:Genetic Markers; D002084:Butylated Hydroxytoluene