Alterations in the nigrostriatal dopamine system after acute systemic PhIP exposure
Alterations in the nigrostriatal dopamine system after acute systemic PhIP exposure
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DOI：
10.1016/j.toxlet.2018.01.017
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发表时间：
2018-05-01
影响因子：
3.5
通讯作者：
Cannon, Jason R.
中科院分区：
文献类型：
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作者：
Agim, Zeynep Sena;Cannon, Jason R.
杂环胺（HCAs）主要在高温下烹饪肉类时形成。HCAs作为诱变剂和可能的致癌物已被广泛研究。新出现的数据表明，HCAs是神经毒性的，可能与帕金森病（PD）的病因。然而，大多数HCA尚未进行体内神经毒性评价。本文研究了2-氨基-1-甲基-6-苯基咪唑[4，5-B]吡啶（PhIP）的急性体内神经毒性。PhIP是许多肉类中最常见的遗传毒素。成年雄性Sprague-Dawley大鼠在癌症研究中广泛使用的剂量和时间点（100和200 mg/kg，持续8、24 h）接受急性全身PhIP，并评价多巴胺能、胆碱能、GABA能和多巴胺能神经传递的变化。PhIP暴露导致纹状体多巴胺代谢物水平和多巴胺周转率降低，而囊泡单胺转运蛋白2水平没有变化;其他神经递质系统不受影响。细胞内硝基酪氨酸的定量显示，在黑质多巴胺能神经元的氧化损伤水平较高的PhIP曝光后，而其他神经元群体的敏感性较低。这些变化发生在没有明显病变的黑质纹状体多巴胺系统。总的来说，我们的研究表明，急性PhIP治疗在体内的目标是黑质纹状体多巴胺能系统和PhIP应进一步检查在慢性，低剂量的研究PD的相关性。
Heterocyclic amines (HCAs) are primarily formed during cooking of meat at high temperature. HCAs have been extensively studied as mutagens and possible carcinogens. Emerging data suggest that HCAs are neurotoxic and may be relevant to Parkinson's disease (PD) etiology. However, the majority of HCAs have not been evaluated for in vivo neurotoxicity. Here, we investigated acute in vivo neurotoxicity of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP). PhIP is the most prevalent genotoxin in many types of meats. Adult, male Sprague-Dawley rats were subjected to acute, systemic PhIP at doses and time-points that have been extensively utilized in cancer studies (100 and 200 mg/kg for 8, 24 h) and evaluated for changes in dopaminergic, serotoninergic, GABAergic, and glutamatergic neurotransmission. PhIP exposure resulted in decreased striatal dopamine metabolite levels and dopamine turnover in the absence of changes to vesicular monoamine transporter 2 levels; other neurotransmitter systems were unaffected. Quantification of intracellular nitrotyrosine revealed higher levels of oxidative damage in dopaminergic neurons in the substantia nigra after PhIP exposure, while other neuronal populations were less sensitive. These changes occurred in the absence of an overt lesion to the nigrostriatal dopamine system. Collectively, our study suggests that acute PhIP treatment in vivo targets the nigrostriatal dopaminergic system and that PhIP should be further examined in chronic, low-dose studies for PD relevance.