Citation:

Alewel, D., T. Jackson, A. Henriquez, Mette C Schladweiler, S. Vance, S. Gavett, A. Astriab Fisher, R. Grindstaff, P. Evansky, AND U. Kodavanti. Serum metabolic and tissue transcriptomic profiling reveal acrolein inhalation variably impacts multi-organ stress responses in male and female rats. Society of Toxicology, Nashville, TN, March 19 - 23, 2023.

Impact/Purpose:

This abstract shows that acute acrolein exposure induces systemic metabolic effects, which are associated with marked nasal and liver injury in rats. These metabolic effects are more pronounced in males when comapred to females.

Description:

Acrolein is a well-studied significant constituent of anthropogenic and wildfire smoke emissions and thus, an environmental risk factor contributing to adverse health outcomes. Acrolein is on EPA’s priority list of hazardous air pollutants and is a sensory irritant associated with adverse cardiopulmonary health effects; however, the ability for acrolein to induce systemic metabolic derangement has not been systematically investigated. Further, sex-specific stress responses are not examined in prior acrolein exposure studies, which in terms of metabolic stress is crucial considering the prevalence of metabolic disease often differs between sexes. In this study, 12-week-old male and female Wistar-Kyoto rats underwent acrolein nose-only inhalation in incremental concentrations (0, 0.1, 0.316, 1 ppm) for 30 min for head-out plethysmography assessment, followed by a 3.5 hr exposure at 3.16 ppm (n=8/group). We performed serum metabolic profiling in males and females, identifying 887 known circulating biomolecules. Males showed extensive alterations in circulating metabolites relating to lipolysis, muscle protein catabolism, and mitochondrial respiration cycle shifts, whereas these markers in females were not changed by acrolein exposure. In males, acrolein exposure induced a release of long-chain polyunsaturated fatty acids and phospholipids, including glycerols and sphingomyelins, into circulation, which ultimately altered acetyl-CoA availability for additional noted changes in TCA cycle intermediates. Although the source of increased circulating short-, medium-, and long-chain acylcarnitines is unclear, it may be linked to altered insulin availability and signaling in muscle and liver. As a classic response to sympathetic activation, muscle protein breakdown was observed through increased metabolites of multiple amino acid families in male rats. Further, increased antioxidant glutathione metabolites, as well as other gamma-glutamyl amino acids, suggested an altered state of redox homeostasis in male rats following acrolein inhalation. Interestingly, several sera microbiome-related biochemicals were significantly increased in acrolein-exposed males, suggesting the observed stress response may interact with enteric microbiome processes that respond to environmental stressors. Adrenal corticosterone metabolites, including 11-dehydrocorticosterone, were three-fold higher in acrolein-exposed males, but not females, relative to air control, indicating clear sex-specific glucocorticoid involvement in observed catabolic metabolomic changes. The alterations induced by acrolein in males were confirmed through transcriptomic analysis of liver, adipose, and muscle tissue, supporting trends in sympathetic and glucocorticoid stress responses observed in serum metabolic profiling. In conclusion, acute acrolein inhalation orchestrated a multi-organ metabolic stress response in males, impacting multiple homeostatic metabolic pathways. Basal sex differences in relative metabolite quantity were pervasive throughout all metabolic super-pathways, suggesting a further need to understand how basal metabolism between males and females may impact the stress response, as well as susceptibility to metabolic diseases from exposure to irritant air pollutants. Importantly, male rats showing an increased susceptibility to respiratory-irritation induced metabolic effects relative to female rats may have implications for sex-specific risk of metabolic disease from acrolein and other volatile irritant pollutants (Does not reflect US EPA policy).

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