Abstract：
Fmr1 (fragile X messenger ribonucleoprotein 1)-knockout (KO) rats, modeling the human Fragile X Syndrome (FXS), are of particular interest for exploring the ASD-like phenotype in preclinical studies. Gestational exposure to chlorpyrifos (CPF) has been associated with ASD diagnosis in humans and ASD-like behaviors in rodents and linked to the microbiota-gut-brain axis. In this study, we have used both Fmr1-KO and wild-type male rats (F2 generation) at postnatal days (PND) 7 and 40 obtained after F1 pregnant females were randomly exposed to 1 mg/kg/mL/day of CPF or vehicle. A nuclear magnetic resonance (NMR) metabolomics approach together with gene expression profiles of these F2 generation rats were employed to analyze different brain regions (such as prefrontal cortex, hippocampus, and cerebellum), whole large intestine (at PND7) and gut content (PND40). The statistical comparison of each matrix spectral profile unveiled tissue-specific metabolic fingerprints. Significant variations in some biomarker levels were detected among brain tissues of different genotypes, including taurine, myo-inositol, and 3-hydroxybutyric acid, and exposure to CPF induced distinct metabolic alterations, particularly in serine and myo-inositol. Additionally, this study provides a set of metabolites associated with gastrointestinal dysfunction in ASD, encompassing several amino acids, choline-derived compounds, bile acids, and sterol molecules. In terms of gene expression, genotype and gestational exposure to CPF had only minimal effects on decarboxylase 2 (gad2) and cholinergic receptor muscarinic 2 (chrm2) genes.
摘要：
Fmr1(脆性X信使核糖核蛋白1)敲除(KO)大鼠,对人类脆性X综合征(FXS)进行建模，对于在临床前研究中探索ASD样表型特别感兴趣。妊娠暴露于毒死蜱（CPF）与人类的ASD诊断和啮齿动物的ASD样行为有关，并与微生物群-肠-脑轴有关。在这项研究中,我们在出生后第7天(PND)和第40天使用了Fmr1-KO和野生型雄性大鼠(F2代)，在F1怀孕雌性随机暴露于1mg/kg/mL/天的CPF或载体后获得。核磁共振（NMR）代谢组学方法与这些F2代大鼠的基因表达谱一起用于分析不同的大脑区域（例如前额叶皮质，海马体,和小脑)，整个大肠（在PND7）和肠道含量（PND40）。每个矩阵光谱图的统计比较揭示了组织特异性代谢指纹。在不同基因型的脑组织中检测到一些生物标志物水平的显著差异，包括牛磺酸,肌醇,和3-羟基丁酸，暴露于CPF诱导了明显的代谢改变，特别是丝氨酸和肌醇。此外,这项研究提供了一组与ASD胃肠功能障碍相关的代谢物，包括几种氨基酸，胆碱衍生化合物，胆汁酸，和甾醇分子。在基因表达方面，基因型和妊娠暴露于CPF对脱羧酶2（gad2）和胆碱能受体毒蕈碱2（chrm2）基因的影响很小。
