基于遗传的对百草枯神经毒性的差异易感性在小鼠中。
Genetic-based, differential susceptibility to paraquat neurotoxicity in mice.
机构信息
Intercollege Graduate Degree Program in Neuroscience, The Pennsylvania State University, University Park, PA 16802, USA.
出版信息
Neurotoxicol Teratol. 2011 May-Jun;33(3):415-21. doi: 10.1016/j.ntt.2011.02.012. Epub 2011 Feb 28.
Paraquat (PQ) is an herbicide used extensively in agriculture. This agent is also suspected to be a risk factor for Parkinson's disease (PD) by harming nigro-striatal dopamine neurons. There is likely, genetic-based, individual variability in susceptibility to PQ neurotoxicity related PD. In this study, we measured the delivery of PQ to the brain after three weekly injections of PQ at 5 mg kg(-1), PQ-related neural toxicity after three weekly injections of PQ at 1 mg kg(-1)or 5 mg kg(-1), PQ-related iron accumulation and PQ-related gene expression in midbrain of DBA/2J (D2) and C57BL/6J (B6) inbred mouse strains after a single injection of PQ at 15 mg kg(-1) and 10 mg kg(-1), respectively. Results showed that compared to controls, PQ-treated B6 mice lost greater numbers of dopaminergic neurons in the substantia nigra pars compacta than D2 mice; however, distribution of PQ to the midbrain was equal between the strains. PQ also significantly increased iron concentration in the midbrain of B6 but not D2 mice. Microarray analysis of the ventral midbrain showed greater PQ-induced changes in gene expression in B6 compared to D2 mice. This is the first study to report genetically-based differences in susceptibility to PQ neurotoxicity and to understanding individual differences in vulnerability to PQ neurotoxicity and its relation to PD in humans.
百草枯（PQ）是一种广泛用于农业的除草剂。该药剂还被怀疑是帕金森病（PD）的一个风险因素，因为它会损害黑质纹状体多巴胺神经元。个体对与百草枯毒性相关的 PD 的易感性可能存在基于遗传的个体差异。在这项研究中，我们测量了每周三次注射 5mg/kg 的 PQ 后，PQ 对大脑的输送；每周三次注射 1mg/kg 或 5mg/kg 的 PQ 后 PQ 相关的神经毒性；单次注射 15mg/kg 和 10mg/kg 的 PQ 后，DBA/2J（D2）和 C57BL/6J（B6）近交系小鼠中 PQ 相关的铁积累和 PQ 相关基因表达。结果表明，与对照组相比，与 D2 小鼠相比，PQ 处理的 B6 小鼠黑质致密部失去了更多的多巴胺能神经元；然而，两种品系的 PQ 向中脑的分布是相等的。PQ 还显著增加了 B6 而不是 D2 小鼠中脑的铁浓度。腹侧中脑的微阵列分析显示，与 D2 小鼠相比，B6 小鼠中 PQ 诱导的基因表达变化更大。这是第一项报道基于遗传的对 PQ 神经毒性易感性差异的研究，并有助于理解个体对 PQ 神经毒性及其与人类 PD 易感性的差异。
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