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Toxicol Appl Pharmacol. 2017 Dec 1;336:8-19. doi: 10.1016/j.taap.2017.09.023. Epub 2017 Oct 5.

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

Author information

1
Department of Toxicology & Pharmacology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200, MD, Maastricht, The Netherlands.
2
Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
3
Analytical and Environmental Sciences Division, MRC-PHE Centre for Environmental & Health, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
4
Department of Toxicology & Pharmacology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200, MD, Maastricht, The Netherlands. Electronic address: R.Godschalk@maastrichtuniversity.nl.

Abstract

Patients with inflammatory lung diseases are often additionally exposed to polycyclic aromatic hydrocarbons like B[a]P 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, 20μg/mouse) to induce pulmonary inflammation and subsequently exposed to B[a]P (0.5mg/mouse) by intratracheal instillation. Gene expression 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.

KEYWORDS:

Benzo[a]pyrene (B[a]P); Lipopolysaccharide (LPS); Mouse lung; RNA microarray

PMID:
28987381
PMCID:
PMC5703654
DOI:
10.1016/j.taap.2017.09.023
[Indexed for MEDLINE]
Free PMC Article

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