Delayed and non-linear systemic effects of mixed alumina nanoparticle and hydrogen chloride inhalation revealed by metabolomics

Le résumé fourni par la source

Combustion of solid propellants releases alumina nanoparticles (Al₂O₃ NPs) and hydrogen chloride gas (HCl g ), raising concerns for exposed personnel. Conventional markers often lack sensitivity to detect subtle systemic effects that may precede overt toxicity. To address this gap, we combined classical toxicological endpoints with serum ¹H NMR metabolomics and interpreted the results as a mechanistic hypothesis rather than a formal adverse outcome pathway (AOP). Male Wistar rats were exposed nose-only (4 h/day, 4 days) to air or mixtures of Al₂O₃ NPs (1, 5, or 20 mg/m³) and HCl g (5 ppm). Body and organ weights, hematology, serum biochemistry, and inflammatory markers were measured at day 1 and day 28 post-exposure, while serum metabolomics profiles were analyzed using multivariate and univariate statistics with pathway enrichment. Conventional markers showed only minor and inconsistent variations with no evidence of systemic toxicity. In contrast, metabolomics analysis revealed delayed, coordinated, and non-linear systemic alterations, strongest at the intermediate mixture concentration (5 mg/m³ Al₂O₃ NPs + 5 ppm HCl g ). Key metabolites such as cytidine, formate, methanol, and valerate decreased at day 28, while pathway disruptions involving glycolysis, pyrimidine, and folate metabolism were identified. Correlation network analysis supported coordinated alterations of energy and nucleotide pathways. Overall, serum metabolomics analysis revealed subtle, delayed and non-monotonic systemic metabolic alterations under mixture exposure that remained invisible to standard markers. These findings demonstrate the higher sensitivity of metabolomics for evaluating the systemic impact of inhalable mixtures and support the proposal of a mechanistic hypothesis that may contribute to the understanding of systemic responses to inhalation mixtures.

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