The mechanism of selenomethionine alleviating fluoride-induced brain injury in carp by regulating mitochondrial dynamics, oxidative stress and neuroinflammation: Integrated analysis of transcriptomics and metabolomics.

This study was designed to clarify the protective effect of selenomethionine (Se-Met) and the underlying molecular mechanism on brain injury induced by fluoride (F) in carp. Using carp as the model organism, F injury model and Se-Met intervention models were established. Physiological and biochemical indicators (antioxidant enzyme activities, ATP synthesis efficiency, etc.), molecular biological analysis (apoptosis- and inflammation- related gene expression) and as well as transcriptomics and metabolomics technology were integrated to comprehensively investigate the pathological process of F-induced brain injury and the protective mechanism of Se-Met. The results showed that F significantly activated the NF-κB signaling pathway, induced mitochondrial dynamics imbalance (DRP1 up-regulation/MFN1 down-regulation), oxidative stress (decreased activities of GSH, SOD; increased MDA) and neuroinflammation (up-regulation of IL-1β, TNF-α; down-regulation of IL-10), eventually leading to neuronal apoptosis and behavioral disorders. Se-Met intervention effectively reversed these toxic effects through multiple pathways, specifically by restoring antioxidant enzyme activities (T-SOD, CAT, GSH-Px, GSH); Se-Met up-regulated the expression of anti-apoptotic gene Bcl-2 and down-regulated the expression of pro-apoptotic genes Bax and caspase-3 to inhibit neuronal apoptosis; Se-Met inhibited NLRP3 inflammasome activation and reduced the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-1α, IL-10, TGF-β); Se-Met balanced mitochondrial dynamics protein (DRP1/MFN1) expression and restored mitochondrial function (ATP and membrane potential recovery); Se-Met reversed abnormal expression of neuropeptides (GnRH-II, vip, PDYN). The integrated analysis of metabolomics and transcriptomics further revealed that Se-Met exerted neuroprotective effects by regulating calcium signaling pathway, arachidonic acid metabolism and neuroactive ligand-receptor interaction pathway. However, long-term exposure to Se-Met alone may also cause mild toxicity, indicating that its application requires strict control of dosage and exposure duration. This study elucidates the molecular mechanisms by which Se-Met mitigates F neurotoxicity and provides a theoretical basis for aquatic ecological risk assessment and selenium nutrition intervention strategies.