The MT1G Gene in LUHMES Neurons Is a Sensitive Biomarker of Neurotoxicity.
The MT1G Gene in LUHMES Neurons Is a Sensitive Biomarker of Neurotoxicity.
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DOI：
10.1007/s12640-020-00272-3
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发表时间：
2020-12
影响因子：
3.7
通讯作者：
Gerhold D
中科院分区：
文献类型：
--
作者：
Tong ZB;Braisted J;Chu PH;Gerhold D
神经系统疾病的基础毒物的识别是一个被忽视的领域，等待一个有效的战略，以确定这样的毒物。我们寻找对LUHMES永生化神经元中已知神经毒物有反应的生物标志物，并评估这些生物标志物用于筛选环境毒物库。在用帕金森病毒物鱼藤酮、6-羟基多巴胺、MPP+和福美锌（二甲基二硫代氨基甲酸锌; Zn 2 + DDC 2）以及其他毒物百草枯、MS 275和甲基汞激发后，通过RNA测序对LUHMES永生化的人多巴胺能神经元进行了研究。金属硫蛋白基因MT 1G是对所有7种毒物最动态的基因表达反应。多种毒物还增加了SLC 30 A1和SLC 30 A2锌分泌转运蛋白、对谷胱甘肽合成重要的SLC 7A 11 xCT胱氨酸/谷氨酸反向转运蛋白、DNA损伤诱导转录物3（DDIT 3）和分泌的生长因子FIB IN和CXCL 12的转录物，而几种毒物降低了爱帕琳生长因子（APLN）的表达。这些生物标志物基因揭示了在亚细胞毒性浓度下对许多毒物的应激反应。由于这些生物标志物基因中的几个和先前的神经系统疾病研究涉及金属分布的破坏，我们测试了金属螯合剂福美双（二甲基二硫代氨基甲酸酯，DDC），福美双，和其他几种金属和金属螯合物的细胞毒性和MT 1G表达的诱导。引起MT 1G表达动态增加的金属和螯合剂也引起细胞毒性，除了Ni 2 + DDC 2在5 μM时诱导MT 1G，但在高达100 μM时缺乏细胞毒性。这些结果支持了先前的工作，表明神经元对谷胱甘肽的耗尽或细胞金属分布的破坏具有特征性的敏感性，并提供了在化学文库中寻找这种神经毒物的生物标志物。
Identification of toxicants that underlie neurological diseases is a neglected area awaiting a valid strategy to identify such toxicants. We sought biomarkers that respond to known neurotoxicants in LUHMES immortalized neurons and evaluated these biomarkers for use in screening libraries of environmental toxicants. LUHMES immortalized human dopaminergic neurons were surveyed by RNA sequencing following challenge with parkinsonian toxicants rotenone, 6-hydroxydopamine, MPP+, and ziram (zinc dimethyldithiocarbamate; Zn2+DDC2), as well as additional toxicants paraquat, MS275, and methylmercury. The metallothionein gene MT1G was the most dynamic gene expression response to all seven toxicants. Multiple toxicants also increased transcripts for SLC30A1 and SLC30A2 zinc secretion transporters, the SLC7A11 xCT cystine/glutamate antiporter important for glutathione synthesis, DNA damage inducible transcript 3 (DDIT3), and secreted growth factors FIBIN and CXCL12, whereas several toxicants decreased expression of the apelin growth factor (APLN). These biomarker genes revealed stress responses to many toxicants at sub-cytotoxic concentrations. Since several of these biomarker genes and prior neurological disease studies implicated disruption of metal distribution, we tested metal chelator thiram (dimethyldithiocarbamate, DDC), ziram, and several other metals and metal chelates for cytotoxicity and induction of MT1G expression. Metals and chelators that caused dynamic increases in MT1G expression also caused cytotoxicity, except Ni2+DDC2 induced MT1G at 5 μM, but lacked cytotoxicity up to 100 μM. These results bolster prior work suggesting that neurons are characteristically sensitive to depletion of glutathione or to disruption of cellular metal distribution and provide biomarkers to search for such neurotoxicants in chemical libraries.
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DOI：
10.1016/j.jtemb.2014.07.023
发表时间：
2015
期刊：
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)
影响因子：
--
作者：
Grandjean P;Herz KT
通讯作者：
Herz KT
影响因子：
3.4
作者：
Hardyman, J. E. J.;Tyson, J.;Ford, D.
通讯作者：
Ford, D.
影响因子：
6.2
作者：
Miyazaki, Ikuko;Asanuma, Masato;Kita, Taizo
通讯作者：
Kita, Taizo
影响因子：
2.9
作者：
ODELSTAD, L;PAHLMAN, S;GROTTE, G
通讯作者：
GROTTE, G
影响因子：
8.3
作者：
OSKARSSON, A
通讯作者：
OSKARSSON, A