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Repeated Exposure to Eucalyptus Smoke Alters Pulmonary Gene and Metabolic Profiles in Male Long-Evans Rats
Citation:
Dunigan-Russell, K., H. Nguyen, J. Dye, H. Ren, Mette C. Schladweiler, D. Jones, A. Fisher, Ian Gilmour, K. Gowdy, C. Miller, AND M. Smith. Repeated Exposure to Eucalyptus Smoke Alters Pulmonary Gene and Metabolic Profiles in Male Long-Evans Rats. Society of Toxicology, San Diego, California, March 27 - 31, 2022.
Impact/Purpose:
With the increasing prevalence and intensity of wildland fires in the U.S., there is significant concern for respiratory heath in occupational and public health settings. Wildfires increase toxins in the air including ultrafine particulate matter (PM2.5), noxious gases, and volatile organic chemicals, which are known to increase lung inflammation and injury.
Description:
With the increasing prevalence and intensity of wildland fires in the U.S., there is significant concern for respiratory heath in occupational and public health settings. Wildfires increase toxins in the air including ultrafine particulate matter (PM2.5), noxious gases, and volatile organic chemicals, which are known to increase lung inflammation and injury. Therefore, we hypothesize that wildfire smoke inhalation induces pulmonary genetic and metabolic adaptations through inflammatory signaling. To test this hypothesis, adult male Long-Evans rats were exposed to filtered air or smoke from eucalyptus biomass burning under smoldering conditions at a particle (32nm – 10.57µm) concentration of 11 ± 1.89 mg/m3 (low) or 23.7 ± 0.77 mg/m3 (high) for 1 hr/day for 2 weeks. 24hrs following the last exposure, rats were euthanized and bronchoalveolar lavage (BAL) fluid and lung tissue were collected. BAL was used to measure differential cell counts, cyto/chemokine production in the airspace, as well as inflammatory gene expression in BAL cells. Lung tissues were assessed for changes in gene expression using RNA-seq paired with high-resolution metabolomics (HRM) (n=7-8/group). Differentially expressed genes (DEGs) were identified and analyzed by Ingenuity Pathway Analysis (IPA). BAL cell differentials revealed a dose dependent increase in macrophages, neutrophils and lymphocytes following smoke exposure. Interferon-gamma (IFN-¿), and anti-inflammatory cytokines interleukin-10, IL-5 were also increased in the airspace following low and high smoke inhalation. RNA-seq analysis revealed 1,712 upregulated DEGs and 1,413 downregulated DEGs in the high exposure smoke compared to filtered air. IPA analyses showed increased EIF2 and Rho Family GTPases with reductions in the eIF4, p7056K, and mTOR Signaling. HRM revealed perturbations to 23 metabolic pathways including nucleotide, amino and fatty acids, nitrogen and antioxidant pathways with smoke exposure. Integrative analysis of the transcriptome and metabolome data revealed significant changes in Wnt, NOS1, and Cox2 following smoke exposure. Our results suggest that acute exposures to wildfire smoke results in robust changes to the lung at both the genetic and metabolic levels. These results provide novel insight into the pulmonary response to wildfire smoke and support the association between wildland fire smoke exposure and adverse respiratory outcomes. This abstract does not reflect U.S. EPA policy.