Pulmonary exposure to nanomaterials dysregulates inflammatory lipid mediators in a sex- and disease-dependent manner

Nanosized particles can remain airborne for extended periods of time, travel great distances, and pose health risks upon exposure. Previously, we found that a metabolic syndrome (MetS) male mouse model exhibits increased lung inflammation 24 hours after exposure to silver nanoparticles (AgNPs), compared to a healthy male mouse model. This susceptibility was associated with alterations in specific lipid mediators involved in inflammatory processes. Sex differences exist in lipid regulation and responses to inhaled exposures such as ozone and particulate matter, and these sex variations may also influence susceptibility to nanoparticle inhalation exposures. Further, as with males, the prevalence of MetS in females has risen drastically and may influence exposure-induced susceptibility. Our current study hypothesized exposure to NPs differentially modulates inflammatory responses and lipid regulation in sex- and disease-specific manners resulting in altered susceptibility. Healthy and MetS mice models of both sexes were exposed to 50 μg per mouse of AgNP and CB via oropharyngeal aspiration. Endpoints of toxicity, inflammation, and lipid dysregulation were evaluated 24 hours post-exposure. Exposure to CB resulted in minimal modulation of inflammatory responses in both male and female models. Analysis of bronchoalveolar lavage fluid (BALF) revealed an exacerbation of AgNP-induced neutrophilic influx to MetS in both sexes compared to healthy mice, while female MetS mice demonstrated elevated neutrophilia compared to male MetS mice. Additionally, enhanced pro-inflammatory mRNA expression of interleukin-6 (IL-6), Chemokine (C-C motif) ligand 2 (CCL-2), and chemokine (C-X-C motif) ligand 2 (CXCL-2) was observed to MetS, with exacerbation occurring in AgNP-exposed female mice compared to male mice. The increases in inflammatory markers in female MetS following AgNP exposure was associated with modulation of lipid- metabolizing enzymes such as COX-2 and ALOX-15. MRM profiling, lipid pathway assessment, and targeted lipid analysis demonstrated exposures uniquely modulated lipid regulation dependent on disease, sex, and particle type. Overall, notable sex differences were identified, particularly in the presence of MetS, indicating a sex-specific vulnerability linked to the underlying disease. These findings indicated a heightened pulmonary inflammatory response in females with MetS compared to their male counterparts during AgNP exposure associated with unique lipid dysregulation. Not applicable.