Altered gene expression profiles in the lungs of benzo [a]pyrene-exposed mice in the presence of lipopolysaccharide-induced pulmonary inflammation

Q. Shi, R. R. Fijten, D. Spina, Riffo Y. Vasquez, V. M. Arlt, R. W. Godschalk*, F. J. Van Schooten

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Web of Science)

Abstract

Patients with inflammatory lung diseases are often additionally exposed to polycyclic aromatic hydrocarbons like B[a]l) and B[a]P-induced alterations in gene expression in these patients may contribute to the development of lung cancer. Mice were intra-nasally treated with lipopolysaccharide (LPS, 20 mu g/mouse) to induce pulmonary inflammation and subsequently exposed to B[a]P (0.5 mg/mouse) by intratracheal instillation. Gene expresion changes were analyzed in mouse lungs by RNA microarrays. Analysis of genes that are known to be involved in the cellular response to B[a]P indicated that LPS significantly inhibited gene expression of various enzymes linked to B[a]P metabolism, which was confirmed by phenotypic analyses of enzyme activity. Ultimately, these changes resulted in higher levels of B[a]P-DNA adducts in the lungs of mice exposed to B[a]P with prior LPS treatment compared to the lungs of mice exposed to B[a]P alone. Using principle component analysis (PCA), we found that of all the genes that were significantly altered in their expression, those that were able to separate the different exposure conditions were predominantly related to immune-response. Moreover, an overall analysis of differentially expressed genes indicated that cell-cell adhesion and cell-cell communication was inhibited in lungs of mice that received both B[a]P and LPS. Our results indicate that pulmonary inflammation increased the genotoxicity of B[a]P via inhibition of both phase I and II metabolism. Therefore, inflammation could be a critical contributor to B[a]P-induced carcinogenesis in humans.

Original languageEnglish
Pages (from-to)8-19
Number of pages12
JournalToxicology and Applied Pharmacology
Volume336
DOIs
Publication statusPublished - 1 Dec 2017

Keywords

  • RNA microarray
  • Lipopolysaccharide (LPS)
  • Benzo[a]pyrene (B[a]P)
  • Mouse lung
  • NUCLEOTIDE EXCISION-REPAIR
  • DNA ADDUCT FORMATION
  • POLYCYCLIC AROMATIC-HYDROCARBONS
  • HUMAN CYTOCHROME-P450
  • OXIDATIVE STRESS
  • EPITHELIAL-CELLS
  • IN-VIVO
  • TRANSCRIPTIONAL REGULATION
  • MONOOXYGENASE REACTIONS
  • METABOLIC-ACTIVATION

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