Targeted Metabolomics for the Analysis of p-Cresol in Mouse Brain: Impact of Biological Sex and Strain.

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Chemical Neuroscience Pub Date : 2025-02-05 Epub Date: 2025-01-19 DOI:10.1021/acschemneuro.4c00698
Laura Bertarini, Federico Imbeni, Antonietta Vilella, Silvia Alboni, Federica Pellati
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Abstract

p-Cresol, an environmental contaminant and endogenous metabolite derived primarily from the conversion of l-tyrosine by intestinal microflora, is gaining increasing attention, due to its potential impact on human health. Recent studies have highlighted elevated levels of p-cresol and its metabolites, including p-cresyl sulfate and p-cresyl glucuronide, in various populations, suggesting a correlation with neurodevelopmental and neurodegenerative conditions. While the role of this compound as a uremic toxin is well established, its presence and concentration within the central nervous system (CNS) remain largely unexplored. To address this gap, an high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method was optimized and validated for the first time in this work for the targeted metabolomics of p-cresol in brain tissues. This method enabled the quantification of this compound in different brain areas of adult male and female C57BL/6J mice and in the cortex of various mouse strains, including CD-1 and the idiopathic autism model BTBR T+Itpr3tf/J. Additionally, preliminary analyses of human cortex samples confirmed the presence of p-cresol, suggesting its relevance in human brain health. Moreover, metabolomic analyses have further explored the correlations between p-cresol and neurotransmitters, with a particular focus on dopaminergic and noradrenergic pathways. These findings pave the way for understanding the potential impact of p-cresol on neurochemical networks and its implications for neurodevelopmental and neurodegenerative disorders.

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小鼠脑内对甲酚的代谢组学分析:生物性别和品系的影响。
对甲酚是一种环境污染物和内源性代谢物,主要来自肠道微生物群对l-酪氨酸的转化,由于其对人类健康的潜在影响,正日益受到关注。最近的研究强调了对甲酚及其代谢物(包括对甲酚硫酸盐和对甲酚葡萄糖醛酸盐)在不同人群中的升高水平,这表明对甲酚与神经发育和神经退行性疾病有关。虽然这种化合物作为尿毒症毒素的作用已经确定,但它在中枢神经系统(CNS)中的存在和浓度在很大程度上仍未被探索。为了解决这一空白,本研究首次对高效液相色谱-电喷雾电离-串联质谱(HPLC-ESI-MS/MS)方法进行了优化和验证,用于脑组织中对甲酚的靶向代谢组学分析。该方法可以定量测定成年雄性和雌性C57BL/6J小鼠不同脑区和不同小鼠品系(包括CD-1和特发性自闭症模型BTBR T+Itpr3tf/J)皮质中该化合物的含量。此外,对人类皮层样本的初步分析证实了对甲酚的存在,这表明它与人类大脑健康有关。此外,代谢组学分析进一步探讨了对甲酚和神经递质之间的相关性,特别关注多巴胺能和去甲肾上腺素能途径。这些发现为理解对甲酚对神经化学网络的潜在影响及其对神经发育和神经退行性疾病的影响铺平了道路。
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来源期刊
ACS Chemical Neuroscience
ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
9.20
自引率
4.00%
发文量
323
审稿时长
1 months
期刊介绍: ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research
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