Polar and Organic Phase Modulation of Lipids in Lung and Systemic Tissues Following Silica Particle Pulmonary Exposure in Mice

Abstract

Inhaled exposures to particulate matter are increasingly recognized to perturb lipid metabolism both at the site of deposition and systemically. However, lipidomic assessments following particle inhalation often neglect the polar fraction, potentially omitting amphipathic species such as phospholipids, sphingolipids, and ceramides that may partition into the aqueous phase. This exclusion can obscure key lipidomic signatures relevant to inflammation and toxicity. Silica particles (SiO₂), generated from natural and industrial sources, elicit not only pulmonary toxicity but are also implicated in kidney, cardiovascular, and autoimmune diseases. We hypothesized that SiO₂ exposure disrupts lipidomic signatures in both organic and polar phases across multiple tissues, promoting inflammation and systemic toxicity. To evaluate this, mice were exposed to 1 mg of SiO₂ by oropharyngeal aspiration, with controls receiving water (n = 6/group). At 24 h postexposure, acute toxicity end points and lipidomic modifications were evaluated in the lung, liver, kidney, brain, and serum. Gene expression analyses revealed significant upregulation of inflammatory markers in the lung and lipid metabolism dysregulation, specifically an upregulation of prostaglandin-endoperoxide synthase 2 (COX-2), across all evaluated tissues following SiO₂ exposure. Lipidomic results revealed widespread remodeling in both organic and polar fractions due to SiO₂, with the lung showing the greatest magnitude of change. Polar-phase alterations were dominated by glycerophospholipids, whereas the organic fraction reflected shifts in triglycerides and diglycerides. Summed-phase analyses uncovered additional differences not apparent when either phase was assessed independently and revealed distinct lipidomic profiles between control and SiO₂-exposed mice. Moreover, numerous lipid species shared between groups exhibited significant abundance differences. Together, these findings indicate that acute SiO₂ inhalation induces coordinated lipid alterations across organ systems, linking pulmonary exposure to systemic responses. Incorporating both organic and aqueous fractions in lipidomic workflows provides a more complete picture of particle-induced dysregulation and may reveal mechanisms linking pulmonary exposure to systemic outcomes.