Serum metabolome and liver transcriptome reveal acrolein inhalation-induced sex-specific homeostatic dysfunction

Acrolein, a respiratory irritant, induces systemic neuroendocrine stress. However, peripheral metabolic effects have not been examined. Male and female WKY rats were exposed to air (0ppm) or acrolein (3.16ppm) for 4hr, followed by immediate serum and liver tissue collection. Serum metabolomics in both sexes and liver transcriptomics in males were evaluated to characterize the systemic metabolic response. Of 887 identified metabolites, >400 differed between sexes at baseline. An acrolein biomarker, 3-hydroxypropyl-mercapturic acid, increased 18-fold in males and 33-fold in females, indicating greater metabolic detoxification in females than males. Acrolein exposure changed 174 metabolites in males but only 50 in females. Metabolic process assessment identified higher circulating free-fatty acids, glycerols, and other lipids in male but not female rats exposed to acrolein. In males, acrolein also increased branched-chain amino acids, which was linked with metabolites of nitrogen imbalance within the gut microbiome. The contribution of neuroendocrine stress was evident by increased corticosterone in males but not females. Male liver transcriptomics revealed acrolein-induced over-representation of lipid and protein metabolic processes, and pathway alterations including Sirtuin, insulin-receptor, acute-phase, and glucocorticoid signaling. In sum, acute acrolein inhalation resulted in sex-specific serum metabolomic and liver transcriptomic derangement, which may have connections to chronic metabolic-related diseases.

Impact/Purpose

Acrolein is one of the hazardous air pollutants on a priority list, however, systemic health effects are not considered in health risk assessment from inhalation exposures. Here we show that acrolein, a nasal irritant, induces sex-specific systemic metabolic derangement, observed through shifts in glucose, lipid, and protein metabolism in male rats. Acrolein-induced metabolic derangement in males but only modest effects in females was associated with higher levels of acrolein detoxification byproduct in the female serum when compared to males. Increases in serum fatty acids and branched-chain amino acids indicate neuroendocrine-mediated effects on adipose lipolysis and muscle protein catabolism, which can impact energetic and inflammatory processes in the liver. The sex-specific increases in male adrenal corticosterone metabolites further highlights the involvement of neuroendocrine mechanisms in orchestrating multi-organ stress reactions following acrolein exposure. Changes in the male liver transcriptome corroborated responses in cholesterol, fatty acid, and protein metabolism, and suggest the liver as a target for circulating metabolite and stress hormones, albeit the long-term implications of these findings in health outcomes like hepatic insulin resistance and non-alcoholic fatty liver disease require further investigation. Nevertheless, this sexually dimorphic systemic metabolomic response to acute acrolein inhalation may explain the susceptibility to metabolic disruption in males.

Citation

Alewel, D., K. Rentschler, T. Jackson, M. Schladweiler, A. Astriab Fisher, P. Evansky, AND U. Kodavanti. Serum metabolome and liver transcriptome reveal acrolein inhalation-induced sex-specific homeostatic dysfunction. Nature Publishing Group, London, UK, 13:21179, (2023). [DOI: 10.1038/s41598-023-48413-w]

DOI: Serum metabolome and liver transcriptome reveal acrolein inhalation-induced sex-specific homeostatic dysfunction