MPTP neurotoxicity is highly concordant between the sexes among BXD recombinant inbred mouse strains.
MPTP neurotoxicity is highly concordant between the sexes among BXD recombinant inbred mouse strains.
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DOI：
10.1016/j.neuro.2016.04.008
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发表时间：
2016-07
期刊：
影响因子：
3.4
通讯作者：
Jones BC
中科院分区：
文献类型：
--
作者：
Alam G;Miller DB;O'Callaghan JP;Lu L;Williams RW;Jones BC
继续我们先前的工作，我们在10个BXD重组近交系雄性小鼠中显示了MPTP神经毒性的广泛菌株差异，我们在9个相同菌株的雌性小鼠中重复了我们的工作。小鼠接受单次s.c.注射12.5mg/kg MPTP或生理盐水。48小时后，解剖纹状体进行神经化学分析。用高效液相色谱法分析纹状体多巴胺（DA）及其代谢产物DOPAC和HVA，纹状体5-羟色胺（5-HT）及其代谢产物5-HIAA。酪氨酸羟化酶（TH）和胶质细胞酸性蛋白（GFAP），星形胶质细胞的蛋白质，增加在星形胶质细胞对神经损伤的反应，使用ELISA测定。MPTP诱导的DA、DOPAC、HVA、TH和GFAP反应存在广泛的遗传变异。我们还进行了主成分分析（PCA）的差值，盐水减去MPTP，DA，DOPAC，HVA和TH和映射的显性主成分的暗示QTL 1号染色体上的同一位置，我们以前观察到的男性。MPTP对DA、HVA和TH的影响在性别间存在显著相关性。我们的研究结果表明，这里使用的系统遗传方法可以帮助研究人员了解性别在个体差异中的作用。同样的方法可以铺平道路，了解和查明遗传基础的病理学归因于毒物的个体差异。这种系统遗传学方法对于阐明基因-环境对神经退行性疾病的贡献具有广泛的意义。
Continuing our previous work in which we showed wide-ranging strain differences in MPTP neurotoxicity in male mice among ten BXD recombinant inbred strains, we replicated our work in females from nine of the same strains. Mice received a single s.c. injection of 12.5 mg/kg MPTP or saline. Forty-eight hours later the striatum was dissected for neurochemical analysis. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, striatal serotonin (5-HT) and its metabolite, 5-HIAA, were analyzed using HPLC. Tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP), an astrocytic protein that increases during the astroglial response to neural injury, were measured using ELISA. There were wide genetic variations in the DA, DOPAC, HVA, TH and GFAP responses to MPTP. We also performed principal component analysis (PCA) on the difference values, saline minus MPTP, for DA, DOPAC, HVA and TH and mapped the dominant principal component to a suggestive QTL on chromosome 1 at the same location that we observed previously for males. Moreover, there were significant correlations between the sexes for the effect of MPTP on DA, HVA, and TH. Our findings suggest that the systems genetic approach as utilized here can help researchers understand the role of sex in individual differences. The same approach can pave the way to understand and pinpoint the genetic bases for individual differences in pathology attributable to toxicants. Such systems genetics approach has broad implications for elucidating gene-environment contributions to neurodegenerative diseases.