Chronic Nitrous Oxide Exposure Disrupts Metabolism in Mice: A Plasma Untargeted Metabolomics Study
J. Jia, Feng-Lin Zhang, Wen Zhang, Congying Liu, Keming Yun, Yu-Jin Wang, Jiangwei Yan
Metabolites May 1, 2026 DOI: 10.3390/metabo16050324 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational animal study (mouse model, untargeted metabolomics) Peer reviewed |
|---|---|
| Population | C57BL/6 mice exposed to nitrous oxide or room air |
| Intervention | Nitrous oxide |
| Dose | 90,000 ppm |
| Duration | 1 h, twice daily for 28 days |
| Key findings | Chronic nitrous oxide exposure in mice produced 35 differential plasma metabolites, with eight candidate biomarkers showing AUC above 0.90. Elevated SOPC and PC(16:0/16:0) suggested disrupted phospholipid remodeling, while reduced DL-tryptophan, creatine, ectoine, indole, His-Ser, and Ile-Pro pointed to altered amino acid metabolism, including the tryptophan-kynurenine pathway. The authors propose these changes, along with vitamin B12, homocysteine, and methylmalonic acid, may serve as a metabolic fingerprint for nitrous oxide exposure. |
Abstract
Background: Nitrous oxide (N2O) is increasingly used as a recreational drug, leading to neurological and systemic toxicities. However, due to the rapid elimination and minimal alteration of nitrogen oxides, the short direct detection window complicates the assessment of N2O exposure.
Method: In this study, we investigated the effects of chronic N2O exposure on plasma metabolites using an untargeted metabolomics approach in a mouse model. C57BL/6 mice were exposed to 90,000 ppm N2O (1 h, twice daily for 28 days) or room air. Plasma samples were analyzed via UHPLC -Triple TOF -MS. Orthogonal partial least squares discriminant analysis (OPLS-DA) and receiver operating characteristic (ROC) curves were used to identify differential metabolites.
Result: A total of 35 differential metabolites were identified. Eight metabolites with an area under the curve (AUC) > 0.90 were selected as candidate biomarkers, including up-regulated SOPC and PC(16:0/16:0) (suggesting disrupted phospholipid remodeling and membrane integrity), and down-regulated DL-tryptophan, creatine, ectoine, indole, His-Ser, and Ile-Pro. Pathway enrichment analysis revealed significant alterations in glycine, serine and threonine metabolism; phenylalanine, tyrosine and tryptophan biosynthesis; protein digestion and absorption; and tryptophan metabolism.
Conclusions: Our data indicate that chronic N2O exposure disrupts multiple amino acid-related metabolic pathways (e.g., tryptophan-kynurenine pathway) and phospholipid homeostasis. The identified metabolite changes, along with vitamin B12, homocysteine, and methylmalonic acid, may constitute a specific metabolic fingerprint for N2O exposure. These findings help reveal the intrinsic mechanistic links underlying metabolic disorders induced by N2O exposure.