ABSTRACT: Air pollutant exposures have been linked to systemic disease; however, underlying mechanisms between single-tissue exposures and systemic responses are poorly understood. A prototypic inducer of stress, ozone causes respiratory and systemic, multiorgan effects through neuroendocrine stress response activation. The goal of the presented study was to assess transcriptomic signatures of multiple tissues and serum metabolomics to understand how neuroendocrine and adrenal-derived stress hormones contribute to multiorgan health outcomes. Male Wistar Kyoto rats (12-13 weeks old) were exposed to filtered air or 0.8 ppm ozone for 4-hours, and blood/tissues were collected immediately post-exposure. Each tissue had distinct expression profile at baseline. Ozone changed (adjusted p-value < .1, absolute fold-change > 50%) 5,102 genes in muscle, 2,516 in adrenals, 1,640 in lung, 1,333 in liver, 1,242 in adrenals and 274 in hypothalamus. Serum metabolomic analysis identified 863 metabolites, of which 447 were significantly altered in ozone-exposed rats (adjusted p-value < .1, absolute fold change > 20%). Although overall hypoxia, GPCR signaling and glucocorticoid signaling pathways were commonly changed in most tissues, gene signatures within overrepresented pathways showed limited overlap between tissues. This pattern suggested the distribution of receptors and transcriptional mechanisms for stress hormones are likely tissue-specific and involve induction of different gene sets with shared initiating triggers. Metabolomic analysis suggested major changes in lipids, amino acids and metabolites linked to gut microbiome, which correlated with transcriptional changes identified through pathway analysis within liver, muscle, and adipose tissues. Systems-level examination of tissue-specific biological mechanisms could further understanding of air pollution-related health consequences.
