Gestational sevoflurane exposure induces amino acid metabolic reprogramming and cognitive deficits in offspring

Sevoflurane is one of the most widely used anesthetics in pediatric medicine; however, accumulating evidence raises critical concerns regarding its potential to induce long-term neurodevelopmental deficits. Despite extensive research, the underlying systemic molecular mechanisms driving these outcomes remain elusive.

Pregnant C57BL/6J mice were exposed to 2.5% sevoflurane for 2 h at embryonic day 14 (E14). Offspring were assessed for spatial learning and anxiety-related behaviors. To reconstruct the molecular landscape of toxicity, we employed an integrative multi-omics approach combining transcriptomics, proteomics, and paired brain-serum metabolomics, complemented by ELISA validation and histopathology.

Sevoflurane-exposed offspring exhibited persistent spatial learning deficits and anxiety-like behaviors. These functional impairments were mirrored by histopathological damage, characterized by disordered neuronal arrangement and reduced Nissl-positive cells in the hippocampus. Consistently, ELISA analysis revealed a pronounced systemic inflammatory response (elevated IL-1β, IL-6, TNF-α). Integrated multi-omics profiling uncovered the molecular basis of these phenotypes, revealing a landscape of neurodevelopmental gene suppression alongside the activation of oxidative stress and inflammatory signaling. Underpinning these multidimensional pathologies, we identified a convergent reprogramming of amino acid metabolism, defined by glutamate depletion and lysine accumulation-metabolic shifts previously implicated in neuroinflammation and cognitive decline. Finally, ectoine and 5-OPPA were consistently depleted in both brain and serum, identifying them as novel concordant biomarkers of anesthetic neurotoxicity.

These findings demonstrate that gestational sevoflurane exposure induces persistent neurocognitive dysfunction in offspring driven by amino acid metabolic reprogramming. The concordant depletion of ectoine and 5-OPPA highlights their potential as minimally invasive biomarkers for anesthetic induced neurodevelopmental injury.