Astrocyte‐specific transcriptome analysis using the ALDH1L1 bacTRAP mouse reveals novel biomarkers of astrogliosis in response to neurotoxicity
Abstract
Neurotoxicology is hampered by the inability to predict regional and cellular targets of toxicant‐induced damage. Evaluating astrogliosis overcomes this problem because reactive astrocytes highlight the location of toxicant‐induced damage. While enhanced expression of glial fibrillary acidic protein is a hallmark of astrogliosis, few other biomarkers have been identified. However, bacterial artificial chromosome ‐ translating ribosome affinity purification (bacTRAP) technology allows for characterization of the actively translating transcriptome of a particular cell type; use of this technology in aldehyde dehydrogenase 1 family member L1 (ALDH1L1) bacTRAP mice can identify genes selectively expressed in astrocytes. The aim of this study was to characterize additional biomarkers of neurotoxicity‐induced astrogliosis using ALDH1L1 bacTRAP mice. The known dopaminergic neurotoxicant 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP; 12.5 mg/kg s.c.) was used to induce astrogliosis. Striatal tissue was obtained 12, 24, and 48 h following exposure for the isolation of actively translating RNA. Subsequently, MPTP‐induced changes in this RNA pool were analyzed by microarray and 184 statistically significant, differentially expressed genes were identified. The dataset was interrogated by gene ontology, pathway, and co‐expression network analyses, which identified novel genes, as well as those with known immune and inflammatory functions. Using these analyses, we were directed to several genes associated with reactive astrocytes. Of these, TIMP1 and miR‐147 were identified as candidate biomarkers because of their robust increased expression following both MPTP and trimethyl tin exposures. Thus, we have demonstrated that bacTRAP can be used to identify new biomarkers of astrogliosis and aid in the characterization of astrocyte phenotypes induced by toxicant exposures.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 11, 2019
- Source ID
- 10.1111/jnc.14800
Entities
People
- Alicia R. Locker
- Diane B. Miller
- Gordon Broderick
- James P. O'Callaghan
- Julie Miller
- Kimberly A. Kelly
- Kimberly Sullivan
- Lindsay T. Michalovicz
- Rotem Ben‐hamo
- Saurabh Vashishtha
- Sol Efroni
Organizations
- Bar-Ilan University
- Boston University
- Centers for Disease Control and Prevention
- Congressionally Directed Medical Research Programs
- National Institute for Occupational Safety and Health