TIMP1 mRNA expression is a biomarker of astrogliosis: evidence from multiple neurotoxicants and BAC-TRAP technology

Details

• Personal Author:
  Kelly KA ; Miller DB ; O'Callaghan JP ; Revitsky AR
• Description:
  A characteristic feature of neurotoxicity is the selective and unpredictable damage to specific neural cells. This lack of target identity constitutes a substantial barrier to neurotoxicity detection and characterization. Evaluating astrogliosis overcomes this problem as reactive astrocytes show the location of toxicant-induced damage occurring anywhere in the CNS. Enhanced expression of GFAP is a hallmark of reactive astrocytes; however, few other astrogliosis biomarkers are known. Previously, we introduced ALDH1L1 BAC-TRAP (translating ribosome affinity purification) technology for neurotoxicological evaluation as it allows for characterization of the actively translating transcriptome of astrocytes responding to toxicant-induced neural damage. To begin to characterize the astrocyte injury-response transcriptome, ALDH1L1 BAC-TRAP mice were given a single 12.5 mg/kg s.c. dose of MPTP, a well characterized dopaminergic neurotoxicant that induces significant astrogliosis. Striatal tissue (12, 24 and 48 hrs post MPTP) was subjected to TRAP utilizing an eGFP antibody that only binds to actively translating RNA in astrocytes. Changes induced by MPTP damage were determined by microarray (Illumina Expression BeadChip) and the dataset interrogated using Ingenuity Pathway Analysis. MPTP induced robust transcriptome changes in genes previously identified as astrocyte specific with an 800-fold increase in TIMP1, a finding suggestive of the role of astrocytes in extracellular matrix remodeling. These data were confirmed by qPCR and extended to two additional neurotoxicants, methamphetamine (METH) and kainate (KA). As with MPTP, METH and KA mRNA expression analyses showed large fold increases in TIMP1. Prior treatment with the stress hormone, corticosterone (CORT) is known to increase astrogliosis and damage after METH and to decrease the same measures after KA. TIMP1 expression followed the same pattern. These data suggest that astrocytes function in extracellular matrix degradation and tissue remodeling following neurotoxic insult. [Description provided by NIOSH]
• Subjects:
  Biomarkers Endocrine System Environmental Monitoring Genetics Laboratories Nervous System Nervous System Disorders Occupational Health Safety Toxicology
• Keywords:
  Analytical-processes Cellular-function Cellular-reactions Central-nervous-system-disorders Exposure-assessment Genes Hormones Laboratory-animals Laboratory-techniques Laboratory-testing Nerve-damage Neurotoxicity Recombinant-DNA Tissue-disorders

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  California ; OSHA Region 3 ; OSHA Region 9 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  144
• Issue:
  1
• NIOSHTIC Number:
  nn:20045965
• Citation:
  Toxicologist 2015 Mar; 144(1):327
• Federal Fiscal Year:
  2015
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 54th Annual Meeting and ToxExpo, March 22-26, 2015, San Diego, California
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:202efe1f2363512768aac20072e3d310b66c0d78839a6a934e3cda1e436a8a1129c13fa223ba6b7cbd4dbebb0c9ed1658a9e411d803ade2a94522f36b9a58e80
• Download URL:
  https://stacks.cdc.gov/view/cdc/201171/cdc_201171_DS1.pdf
• File Type:
  [PDF - 227.60 KB ]