19 Metabolic disease and sex reconfigure lipid-mediated susceptibility to inhaled particles

Abstract Inhaled particulate toxicity is enhanced in females and those with chronic underlying disease. Metabolic diseases are prevalent, and females have a higher prevalence than males before menopause. Our previous research demonstrated particle-induced lipid dysregulation contributes to the susceptibility observed in males with metabolic syndrome (MetS). Females exhibit sex-specific variations in their lipidome, lipid metabolism, and responses to statins. We hypothesize variations in lipid regulation contribute to particulate susceptibility when females suffer from MetS. To evaluate this hypothesis male and female mice were fed a healthy or high-fat western diet. Mice were then exposed to 50μg of silver nanoparticles (AgNPs) or carbon black (CB), or vehicle control. Samples collected post-exposure were used to determine pulmonary inflammation and lipid dysregulation. Model characterization determined high-fat diet-induced elevations in MetS markers which were more pronounced in males compared to females. Pulmonary injury was identified in males and females exposed to AgNPs while limited CB effects were observed. MetS enhanced neutrophilia in males and females with females demonstrating an enhanced response. Inflammatory gene expression and protein levels were induced in both males and females exposed to AgNPs with exacerbation in MetS females. Compared to AgNPs, limited alterations were observed due to CB; however, effects were more pronounced in females and MetS groups. Gene expression of lipid metabolism enzymes was enhanced in females and MetS models. Pulmonary lipids presented with sex-, disease-, and particle-specific alterations suggesting dysregulation of unique pathways. Overall, this study suggests enhanced susceptibility in females due to MetS providing rationale for interventions.