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Series GSE150005 Query DataSets for GSE150005
Status Public on Aug 11, 2020
Title The MT1G gene in LUHMES Neurons is a Sensitive Biomarker of Neurotoxicity
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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 showed advantages in sensitivity by responding 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), Zn2+DDC2, and several other metals and metal chelates for cytoxicity and induction of MT1G expression. Metals and chelators that caused dynamic increases in MT1G expression caused cytotoxicity, whereas Ni2+DDC2 caused MT1G increase, but no cytotoxicity. 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.
Overall design Dopaminergic neurons differentiated from LUHMES cells were exposed to a vehicle control or one of seven different toxicants. The vehicle control and 7 toxicants were tested on cultured cells in triplicate for a total of 24 biological samples (3 control, 21 toxicant treated samples). Cells were treated for 6 hours prior to initiation of sample prep and RNA extraction.
Contributor(s) Tong Z, Braisted JC, Chu P, Gerhold D
Citation(s) 32870474
Submission date May 06, 2020
Last update date Sep 02, 2020
Contact name David Lee Gerhold
Phone 301-827-5346
Organization name NCATS/NIH
Department Division of Preclinical Innovation
Lab Toxicogenomics Laboratory
Street address 9800 Medical Center Drive
City Rockville
State/province MD
ZIP/Postal code 20850
Country USA
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (24)
GSM4520589 S1_LUHMES_diff_DopaNeuron_DMSO_1
GSM4520590 S2_LUHMES_diff_DopaNeuron_DMSO_2
GSM4520591 S3_LUHMES_diff_DopaNeuron_DMSO_3
BioProject PRJNA630786
SRA SRP260342

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Supplementary file Size Download File type/resource
GSE150005_Tong_et_al_DopaNeuron_PD_Tox_NORMALIZED_MATRIX.txt.gz 3.7 Mb (ftp)(http) TXT
GSE150005_Tong_et_al_DopaNeuron_PD_Tox_RAW_COUNT_MATRIX.txt.gz 1.8 Mb (ftp)(http) TXT
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