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Proteomic analysis of brain regions of adult Long-Evans rats exposed to kainic acid#
Citation:
Pitzer, E., G. Jung, W. Padgett, W. Winnik, C. Ganta, H. Jensen, R. Herbert, AND D. Herr. Proteomic analysis of brain regions of adult Long-Evans rats exposed to kainic acid#. Developmental Neurotoxicology Society, N/A - virtual, NC, June 25 - 29, 2022.
Impact/Purpose:
Abstract entails proteomic data that has been assessed for molecular pathways that have been impacted following know neurotoxicant exposure (Kainic acid) in a rat model. Understanding of proteomic signatures and impacted cellular and molecular pathways following chemical exposure can aid in development of adverse outcome pathways which are models that can assist in knowelge and screening of chemicals. In addition this data intends to be used to aid in in vitro to in vivo extrapolation, increasing validity of in vitro NAM assays for the effiencent screening of chemicals.
Description:
We are using protein signature alterations produced by prototypical neurotoxicants, to allow better understanding of the molecular events produced by these compounds. Adult male Long Evans rats were treated with kainic acid (KA; 6 mg/mL, s.c., chosen not to produce myoclonic seizures), vehicle (VC; buffered saline, 0 mg/mL), or were non-injected (cage controls, CC). At 3 or 24h post-exposure rats were perfused with DPBS, brain regions were collected, and stored at -80°C. Hippocampal samples were assessed for proteomic content using Orbitrap LC-MS, and proteins were identified and processed using Proteome Discover 2.4. Pathway analysis was performed using Ingenuity Pathway Analysis (IPA) software (significant protein cutoff levels: ≤ log2(0.8), ≥ log2(1.2), FDR p-value ≤ 0.05). A total of 1894 and 1770 proteins were identified for mapping with IPA, at 3 and 24 h respectively. Of those proteins, 199 and 103 were altered by KA treatment at 3 and 24h, respectively. At 24h the top proteomic inhibited pathways included synaptogenesis signaling pathway, G Beta Gamma signaling, and Ephrin receptor signaling. Activated pathways at 24h included PTEN signaling, semaphoring neuronal repulsive signaling pathway, and autophagy. Histological changes in the hippocampus were examined (Hematoxylin and Eosin stain) in additional rats, treated and sacrificed at 3, 24, or 48h following KA exposure (0 or 6 mg/mL). No hippocampal microscopic lesions were observed. Proteomic signatures revealed several pathways, including neuronal signaling and cell death, to be impacted in the absence of overt histological changes. Abstract of proposed presentation above does not necessarily reflect US EPA policy.