title: Integrative assessment of chlorine-induced acute lung injury in mice.
abstract: The genetic basis for the underlying individual susceptibility to chlorine-induced acute lung injury is unknown. To uncover the genetic basis and pathophysiological processes that could provide additional homeostatic capacities during lung injury, 40 inbred murine strains were exposed to chlorine, and haplotype association mapping was performed. The identified single-nucleotide polymorphism (SNP) associations were evaluated through transcriptomic and metabolomic profiling. Using ≥ 10% allelic frequency and ≥ 10% phenotype explained as threshold criteria, promoter SNPs that could eliminate putative transcriptional factor recognition sites in candidate genes were assessed by determining transcript levels through microarray and reverse real-time PCR during chlorine exposure. The mean survival time varied by approximately 5-fold among strains, and SNP associations were identified for 13 candidate genes on chromosomes 1, 4, 5, 9, and 15. Microarrays revealed several differentially enriched pathways, including protein transport (decreased more in the sensitive C57BLKS/J lung) and protein catabolic process (increased more in the resistant C57BL/10J lung). Lung metabolomic profiling revealed 95 of the 280 metabolites measured were altered by chlorine exposure, and included alanine, which decreased more in the C57BLKS/J than in the C57BL/10J strain, and glutamine, which increased more in the C57BL/10J than in the C57BLKS/J strain. Genetic associations from haplotype mapping were strengthened by an integrated assessment using transcriptomic and metabolomic profiling. The leading candidate genes associated with increased susceptibility to acute lung injury in mice included Klf4, Sema7a, Tns1, Aacs, and a gene that encodes an amino acid carrier, Slc38a4.
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, PA 15219-3130, USA. gleikauf@pitt.edu
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
authors.forename: Hannah
authors.initials: H
authors.lastname: Pope-Varsalona
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Concel
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Liu
authors.forename: Kiflai
authors.initials: K
authors.lastname: Bein
authors.forename: Annerose
authors.initials: A
authors.lastname: Berndt
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Martin
authors.forename: Koustav
authors.initials: K
authors.lastname: Ganguly
authors.forename: An Soo
authors.initials: AS
authors.lastname: Jang
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Brant
authors.forename: Richard A
authors.initials: RA
authors.lastname: Dopico
authors.forename: Swapna
authors.initials: S
authors.lastname: Upadhyay
authors.forename: Y P Peter
authors.initials: YP
authors.lastname: Di
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Zhen
authors.initials: Z
authors.lastname: Hu
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Vuga
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.forename: Danny C
authors.initials: DC
authors.lastname: Alexander
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: McDunn
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Prows
authors.forename: Daren L
authors.initials: DL
authors.lastname: Knoell
authors.forename: James P
authors.initials: JP
authors.lastname: Fabisiak
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000235:genetics*; D000818:Animals; D002713:Chlorine / Q000494:pharmacology*; D002874:Chromosome Mapping / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D000090062:Kruppel-Like Factor 4; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D059467:Transcriptome / Q000235:genetics
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D002713:Chlorine