Citation:

Alewel, D., T. Jackson, K. Rentschler, M. Schladweiler, A. Astriab Fisher, S. Gavett, P. Evansky, AND U. Kodavanti. Differential transcriptomic alterations in nasal versus lung tissue of acrolein-exposed rats. Frontiers in Toxicology. Frontiers, Lausanne, Switzerland, 27(5):1280230, (2023). https://doi.org/10.3389/ftox.2023.1280230

Impact/Purpose:

Acrolein, a volatile aldehyde, is a pollutant frequently encountered by large parts of the population that is implicated in numerous respiratory diseases. Toxicology studies across the literature have parsed together acrolein’s molecular mechanisms of toxicity; however, few studies have provided an unbiased global transcriptional characterization of the airway response. Further, the use of rodents to predict toxicity outcomes in humans presents uncertainty due to species differences in airway morphology and rodents being obligate nose-breathers, where pollutants such as acrolein are expected to deposit in the nose and minimally impact the lung. Thus, a comparative assessment of upper versus lower airway outcomes is needed to improve toxicity evaluation. Here, we identified sex- and site-specific injury/inflammation and cytokine responses, where male rat nasal responses were more sensitive to an acute acrolein exposure compared to females. More importantly, mRNA sequencing in male rats revealed acrolein induces potent pro-inflammatory signaling, cellular organelle stress, and changes in glucocorticoid and GPCR signaling that was unique to the nose. In the lung, small acrolein responses indicated xenobiotic metabolism reactions. Considering acrolein is a potent irritant, these findings demonstrate clear site-specific reactions in rodent airways, which may have implications for those with upper respiratory diseases.  

Description:

Introduction: Acrolein is a significant component of anthropogenic and wildfire emissions, as well as cigarette smoke. Although acrolein primarily deposits in the upper respiratory tract upon inhalation, patterns of site-specific injury in nasal versus pulmonary tissues are not well characterized. This assessment is critical in the design of in vitro and in vivo studies performed for assessing health risk of irritant air pollutants. Methods: In this study, male and female Wistar-Kyoto rats were exposed noseonly to air or acrolein. Rats in the acrolein exposure group were exposed to incremental concentrations of acrolein (0, 0.1, 0.316, 1 ppm) for the first 30 min, followed by a 3.5 h exposure at 3.16 ppm. In the first cohort of male and female rats, nasal and bronchoalveolar lavage fluids were analyzed for markers of inflammation, and in a second cohort of males, nasal airway and left lung tissues were used for mRNA sequencing. Results: Protein leakage in nasal airways of acrolein-exposed rats was similar in both sexes; however, inflammatory cells and cytokine increases were more pronounced in males when compared to females. No consistent changes were noted in bronchoalveolar lavage fluid of males or females except for increases in total cells and IL-6. Acrolein-exposed male rats had 452 differentially expressed genes (DEGs) in nasal tissue versus only 95 in the lung. Pathway analysis of DEGs in the nose indicated acute phase response signaling, Nrf2-mediated oxidative stress, unfolded protein response, and other inflammatory pathways, whereas in the lung, xenobiotic metabolism pathways were changed. Genes associated with glucocorticoid and GPCR signaling were also changed in the nose but not in the lung. Discussion: These data provide insights into inhaled acrolein-mediated sex-specific injury/inflammation in the nasal and pulmonary airways. The transcriptional response in the nose reflects acrolein-induced acute oxidative and cytokine signaling changes, which might have implications for upper airway inflammatory disease susceptibility.

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