global gene transcription in mice after exposure to ethanol and kynurenic acid

Kynurenic acid (KYNA), an unavoidable tryptophan metabolite during fermentation is naturally blended with alcohol in all alcoholic beverages. KYNA has important biological activities from protection of nerve receptors against excessive activation in the central nervous system to suppression of host inflammatory response in the immune system. While alcohol influence of gene transcription has been well studied, the combined effect of alcohol and KYNA has not. The current research has been focused on defining the synergistic effects of alcohol and KYNA on gene expression related to tryptophan metabolism and cell signaling. Adult mice were exposed to alcohol (ethanol) and/or KYNA daily for a week. Gene expression in different tissues (brain, kidney and liver) were profiled. The results indicate that while KYNA alone largely promotes, and alcohol alone mostly inhibits gene expression, alcohol and KYNA co-administration has a stronger inhibition of global gene expression. Tryptophan metabolism is severely skewed towards kynurenine pathway by decreasing tryptophan hydroxylase 2 and increasing tryptophan dioxygenase after ethanol and KYNA co-administration. Measurements of tryptophan metabolic enzymes verified the transcriptional changes of these enzymes. Furthermore, the co-administration greatly enhances the GnRH signaling pathway. These findings provide new insight into the potential impact of alcohol and KYNA on health.

犬尿烯酸（Kynurenic acid, KYNA）是发酵过程中不可避免的色氨酸代谢产物，天然与酒精共存于所有含酒精饮品中。KYNA具有多种重要生物活性，涵盖保护中枢神经系统内的神经受体免受过度激活，以及抑制免疫系统中的宿主炎症反应等范畴。尽管酒精对基因转录的影响已得到广泛研究，但酒精与KYNA的联合作用却尚未被充分探明。本研究旨在阐明酒精与KYNA在色氨酸代谢及细胞信号通路相关基因表达中的协同效应。实验中，成年小鼠每日接受酒精（乙醇，ethanol）和/或KYNA干预，持续一周。随后对大脑、肾脏与肝脏等不同组织的基因表达谱进行了检测分析。研究结果显示：单独使用KYNA可显著促进基因表达，而单独使用酒精则大多抑制基因表达；但酒精与KYNA联合给药时，对全局基因表达的抑制作用更强。联合给予酒精与KYNA后，色氨酸羟化酶2（tryptophan hydroxylase 2）表达下调、色氨酸双加氧酶（tryptophan dioxygenase）表达上调，使得色氨酸代谢显著向犬尿氨酸通路偏移。对色氨酸代谢相关酶的检测结果验证了上述酶的转录水平变化。此外，联合给药还可显著增强促性腺激素释放激素（Gonadotropin-Releasing Hormone, GnRH）信号通路的活性。本研究结果为解析酒精与KYNA对机体健康的潜在影响提供了全新视角。