Systems Genetics and Systems Biology Analysis of Paraquat Neurotoxicity in BXD Recombinant Inbred Mice
Systems Genetics and Systems Biology Analysis of Paraquat Neurotoxicity in BXD Recombinant Inbred Mice
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DOI：
10.1093/toxsci/kfaa050
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发表时间：
2020-07-01
影响因子：
3.8
通讯作者：
Jones, Byron C.
中科院分区：
文献类型：
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作者：
Torres-Rojas, Carolina;Zhuang, Daming;Jones, Byron C.
百草枯 (PQ) 是一种在许多国家（包括美国）使用的除草剂。它还被认为是散发性帕金森病的危险因素，特别是对于那些生活在农业地区并饮用井水的人来说。然而，将 PQ 与散发性帕金森病联系起来的研究并不一致，而且个体间的易感性似乎存在差异。可能的原因之一是亚人群对百草枯神经毒性的易感性存在差异。为了解决这个问题，我们测试了百草枯对小鼠遗传参考群体（BXD 重组近交系家族）的影响。在我们早期的工作中，我们发现，在遗传易感小鼠中，百草枯会增加腹侧中脑（包含黑质的区域）的铁含量。我们的假设是，遗传变异性导致不同的 PQ 相关易感性和铁浓度。为了检验这一假设，我们用百草枯 3 种剂量中的 1 种（1、5 和 10 mg/kg）每周 3 次治疗 28 至 39 种 BXD 品系加上亲代品系的雄性小鼠。在治疗期结束时，我们分析了腹侧中脑的铁、铜和锌浓度，还测量了小脑中百草枯的浓度以及血清和小脑中促炎细胞因子的浓度。 5 mg/kg 百草枯处理小鼠的效果和铁的主成分分析表明，第 5 号染色体上存在数量性状位点。总体而言，我们的结果表明，基因 Prkag2 和相关网络可能作为对抗百草枯毒性的潜在靶点，并证明了遗传多样性小鼠模型在研究复杂的人类毒性方面的实用性。
Paraquat (PQ) is an herbicide used in many countries, including the United States. It is also implicated as a risk factor for sporadic Parkinson's disease, especially in those living in agricultural areas and drinking well water. Studies linking PQ to sporadic Parkinson's disease are not consistent however and there appears to be interindividual differential susceptibility. One likely reason is genetically based differential susceptibility to paraquat neurotoxicity in subpopulations. To address this issue, we tested the effects of paraquat in a genetic reference population of mice (the BXD recombinant inbred strain family). In our earlier work, we showed that in genetically susceptible mice, paraquat increases iron in the ventral midbrain, the area containing the substantia nigra. Our hypothesis is that genetic variability contributes to diverse PQ-related susceptibility and iron concentration. To test this hypothesis, we treated male mice from 28 to 39 BXD strains plus the parental strains with 1 of 3 doses of paraquat, 1, 5, and 10 mg/kg 3 times on a weekly basis. At the end of the treatment period, we analyzed the ventral midbrain for concentrations of iron, copper, and zinc, also we measured the concentration of paraquat in cerebellum, and proinflammatory cytokines in serum and cerebellum. The effect on paraquat-treated mice with 5 mg/kg and principal component analysis of iron showed suggestive quantitative trait loci on chromosome 5. Overall, our results suggest that gene Prkag2 and related networks may serve as potential targets against paraquat toxicity and demonstrate the utility of genetically diverse mouse models for the study of complex human toxicity.