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Soot Nanoparticles Promote Biotransformation, Oxidative Stress, and Inflammation in Murine Lungs

¹ Comparative Biomedical Sciences, ² Division of Biotechnology and Molecular Medicine (BioMMED), and ³ Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana

Correspondence and requests for reprints should be addressed to Arthur Penn, PhD, Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Skip Bertman Drive, Baton Rouge, LA 70803. E-mail: apenn{at}vetmed.lsu.edu

We previously described the physicochemical characteristics (particle size, adsorbed polynuclear aromatic hydrocarbons [PAHs], oxygen, and metal content) of butadiene soot (BDS) nanoparticles generated during incomplete combustion of the high-volume industrial petrochemical, 1,3-butadiene. We also demonstrated localization of BDS-delivered PAHs to lipid droplets of murine and human respiratory cells in vitro and up-regulation of biotransformation and oxidative stress responses in these cells. Here, the objective was to determine whether inhalation of BDS nanoparticles promotes up-regulation of Phase I biotransformation enzymes, oxidative stress responses, and inflammation in the lungs of mice. Female Balb/c mice exposed to BDS (5 mg/m³, 4 h/d, 4 d) were killed immediately or 1 day after final exposure; bronchoalveolar lavage fluid (BALF) was collected from the lungs; total RNA was extracted from one lung and histopathology performed on the other. Histopathology and BALF analysis revealed particle-laden macrophages in airways of BDS-treated mice, accompanied by neutrophilia and epithelial damage. Microarray and qRT-PCR analyses revealed up-regulation of (1) aryl hydrocarbon receptor (AhR)-responsive genes: AhR repressor (Ahrr) and cytochrome P450 IA1 and IB1(Cyp1a1, Cyp1b1); (2) oxidative stress response genes: heme oxygenase 1 (Hmox1), nuclear factor erythroid-derived 2–like 2 (Nfe2l2), NADPH dehydrogenase quinone 1 (Nqo1), and glutathione peroxidase 2 (Gpx2); and (3) pro-inflammatory genes: interleukin-6 (IL-6), C-X-C motif ligand 2 (Cxcl2; analog to human IL-8) and ligand 3 (Cxcl3), and granulocyte chemotactic protein (Cxcl6). Inhalation of PAH-rich, petrochemical combustion–derived nanoparticles causes airway inflammation and induces expression of AhR-associated and oxidative stress response genes, as seen in vitro, plus pro-inflammatory genes.

Key Words: inhalation • combustion nanoparticles • lung inflammation • biotransformation • cytokine genes

CLINICAL RELEVANCE This research describes a novel nanoparticle source of human polynuclear aromatic hydrocarbon inhalation exposure and defines the early molecular events associated with, and in response to, this exposure.