Evaluation of Circadian Rhythm Disturbances in Mice Models with Impaired Heme Biosynthesis Induced by Environmental Chemicals

我们已经开发了一个小鼠模型，肝卟啉症引起的摄入的化学物质，灰黄霉素（GF），并分析了卟啉症模型小鼠的生化和行为表型的特征。卟啉病小鼠体内氨基乙酰丙酸（ALA）和卟啉类血红素前体大量蓄积，并出现肝损伤和皮肤炎症等症状。此外，他们表现出几种神经和心理行为，如焦虑和抑郁，通常在急性卟啉症中观察到。此外，我们发现这些小鼠对精神药物如地西泮的敏感性与对照小鼠不同，而药代动力学没有任何差异。此外，这些小鼠的昼夜活动和温度节律表现出几个小时的相位提前。血红素治疗可改善异常的昼夜节律。总之，我们证明了血红素调节的昼夜节律异常的肝卟啉症的小鼠模型由GF诱导。

We have developed a mouse model of hepatic porphyria induced by ingestion of a chemical substance, griseofulvin (GF), and analyzed the characterization of biochemical and behavioral phenotypes of the porphyria model mice. The porphyria mice exhibited tremendous accumulation of aminolevurinic acid (ALA) and porphyrins asn heme precursors, and also had symptoms, such as liver injury and skin inflammation. In addition, they exhibited several neurological and psychological behaviors, such as anxiety and depression, typically observed in acute porphyria. Moreover, we found that these mice had differential sensitivities to psychological drugs, such as diazepam, comparing to the control mice, without any difference in the pharmacokinetics. Furthermore, circadian activity and temperature rhythms of these mice exhibited phase-advances by a few hours. The abnormal circadian rhythms were ameliorated by the treatment of heme. In conclusion, we demonstrated heme-regulated abnormality of circadian rhythms in the mice model of hepatic porphyria induced by GF.