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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Obesity and Metabolism Research » Research » Publications at this Location » Publication #387495

Research Project: Improving Public Health by Understanding Metabolic and Bio-Behavioral Effects of Following Recommendations in the Dietary Guidelines for Americans

Location: Obesity and Metabolism Research

Title: Diesel exhaust particle extract elicits an oxPAPC-like transcriptomic profile in macrophages across multiple mouse strains

Author
item BHETRARATANA, MAY - University Of California (UCLA)
item OROZCO, LUZ - University Of California (UCLA)
item Bennett, Brian
item LUNA, KARLA - University Of California (UCLA)
item YANG, XIA - University Of California (UCLA)
item LUSIS, ALDONS - University Of California (UCLA)
item ARAUJO, JESUS - University Of California (UCLA)

Submitted to: Environmental Pollution
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/19/2024
Publication Date: 6/20/2024
Citation: Bhetraratana, M., Orozco, L.D., Bennett, B.J., Luna, K., Yang, X., Lusis, A.J., Araujo, J.A. 2024. Diesel exhaust particle extract elicits an oxPAPC-like transcriptomic profile in macrophages across multiple mouse strains. Environmental Pollution. 358. https://doi.org/10.1016/j.envpol.2024.124415.
DOI: https://doi.org/10.1016/j.envpol.2024.124415

Interpretive Summary: Macrophages are attractive candidates to mediate the effects of air pollutants from the lungs to the systemic vasculature. While there are multiple cell types in the lungs, alveolar and interstitial macrophages are among those that initially respond to air pollutants. Our previous work has shown that environmental pollutants markedly dysregulate the gene expression profile of murine macrophages in the C57BL/6 background, both in vitro and in vivo. However, the role of different genetic identities in those responses has not been studied. In the current study, we have used a subset of strains from this panel to analyze molecular pathways mediating macrophage responses to air pollutant chemicals. We isolated peritoneal macrophages from 24 different inbred mouse strains. These cells were then treated with either media only or an organic extract of diesel exhaust particles (DEPe), employed as a model air pollutant or oxidized lipids. We then analyzed their gene expression profiles using Affymetrix microarrays to identify key molecular pathways activated in response to DEPe.

Technical Abstract: Background: Air pollution remains as a prominent cause of cardiopulmonary illness worldwide but the mechanisms mediating those effects and individual susceptibility are unknown. Since macrophages are highly responsive to inhaled particles, we hypothesized that macrophages with different genetic identities vary in their responses against vehicle pollutants. Results: We conducted a genome-wide analysis of peritoneal macrophages harvested from 24 strains of mice from the Hybrid Mouse Diversity Panel (HMDP), and treated them with a methanol extract of DEP (DEPe) to elucidate potential mechanisms that mediate acute effects induced by air pollution exposures. This analysis showed that 1,247 genes were upregulated and 1,383 genes were downregulated with DEPe treatment. Pathway analysis using the Molecular Signatures Database identified oxidative stress-related responses among the most prominent upregulated pathways, and indeed many of the upregulated genes included antioxidants such as Hmox1, Txnrd1, Srxn1, and Gclm. Transcription factor analysis using the Expression2Kinases Web tool showed that NRF2 was the most significant driver of the upregulated genes. DEPe induced a Mox transcriptomic profile, typically induced by oxidized phospholipids, and likely dependent on NRF2 expression. Analysis of individual strains revealed differences in the degree of Mox polarization in each strain, with C57L/J showing the greatest level of Mox polarization. Conclusions: DEPe dysregulated a large number of genes in peritoneal macrophages from multiple strains of mice. Macrophage profiles were dominated by antioxidant responses and a Mox transcriptomic profile across the various strains, likely driven by the transcription factor NRF2. The degree of DEP-induced Mox polarization varied among the HMDP strains. These results may have significant implications in the cardiopulmonary toxicity induced by air pollution.