Untargeted Metabolomic Analysis Reveals the Metabolic Disturbances and Exacerbation of Oxidative Stress in the Cerebral Cortex of a BTBR Mouse Model of Autism.

Scientists studied brain chemistry in mice that model autism behaviors. They found 14 chemical changes in the brain compared to normal mice. These changes affected how the brain processes fats, makes energy, and handles stress. The study suggests that increased harmful chemicals in the brain may damage the parts of cells that make energy, which could contribute to autism symptoms.

This study used untargeted metabolomics to analyze brain tissue from BTBR mice, an established autism model, compared to control mice. Researchers identified 14 significantly altered metabolites in the cerebral cortex, with 5 decreased and 9 increased compounds. The metabolic changes affected multiple pathways including lipid metabolism, energy production, amino acid processing, and antioxidant systems. Key findings suggest oxidative stress plays a central role in autism pathology, with prooxidant metabolites leading to mitochondrial dysfunction and abnormal energy metabolism.

The study also identified disturbances in sulfur metabolism and carnitine biosynthesis as potential mechanisms underlying autism-related neurological dysfunction and behavioral outcomes.

Findings suggest potential roles for antioxidant interventions and metabolic support targeting mitochondrial function in autism. However, translation from mouse models to human clinical applications requires significant additional research and validation studies.

Single animal model study with unknown sample size limits generalizability to humans. Untargeted metabolomic approach provides correlational rather than causal evidence. No validation in human subjects or other autism models reported.

The etiology and pathology of autism spectrum disorders (ASDs) are still poorly understood, which largely limit the treatment and diagnosis of ASDs. Emerging evidence supports that abnormal metabolites in the cerebral cortex of a BTBR mouse model of autism are involved in the pathogenesis of autism. However, systematic study on global metabolites in the cerebral cortex of BTBR mice has not been conducted. The current study aims to characterize metabolic changes in the cerebral cortex of BTBR mice by using an untargeted metabolomic approach based on UPLC-Q-TOF/MS.

C57BL/6 J mice were used as a control group. A total of 14 differential metabolites were identified. Compared with the control group, the intensities of PI(16:0/22:5(4Z,7Z,10Z,13Z,16Z)), PC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/18:1(9Z)), PA(16:0/18:1(11Z)), 17-beta-estradiol-3-glucuronide, and N6,N6,N6-trimethyl-L-lysine decreased significantly (p < 0.01) and the intensities of 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline, LysoPC(20:4(5Z,8Z,11Z,14Z)/0:0), adenosine monophosphate, adenosine-5'-phosphosulfate, LacCer(d18:1/12:0),3-dehydro-L-gulonate, N-(1-deoxy-1-fructosyl)tryptophan, homovanillic acid, and LPA(0:0/18:1(9Z)) increased significantly (p < 0.01) in the BTBR group. These changes in metabolites were closely related to perturbations in lipid metabolism, energy metabolism, purine metabolism, sulfur metabolism, amino acid metabolism, and carnitine biosynthesis.

Notably, exacerbation of the oxidative stress response caused by differential prooxidant metabolites led to alteration of antioxidative systems in the cerebral cortex and resulted in mitochondrial dysfunction, further leading to abnormal energy metabolism as an etiological mechanism of autism. A central role of abnormal metabolites in neurological functions associated with behavioral outcomes and disturbance of sulfur metabolism and carnitine biosynthesis were found in the cerebral cortex of BTBR mice, which helped increase our understanding for exploring the pathological mechanism of autism.