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Changes in the metabolome may serve as peripheral biomarkers of CNS toxicity.
Citation:
Herr, D. Changes in the metabolome may serve as peripheral biomarkers of CNS toxicity. Society of Toxicology, San Antonio, Texas, March 11 - 15, 2018.
Impact/Purpose:
This abstract is for a presentation to be given during a Workshop at SOT in 2018. These data will help design follow-on studies with other known neurotoxicants to be used to assess the broad applicabilty of the present findings. Together this approach represents an effort to develop and qualify a set of translational biochemical markers of neurotoxicity that will be readily accessible in humans.
Description:
Since our observation that an acute exposure to different classes of pesticides resulted in different changes in plasma metabolomics markers, a study of the metabolome has become of high interest for identifying markers of neurotoxicity. A Biocrates AbsoluteIDQTM p180 platform was used for targeted identification of metabolite changes in rat CSF, plasma and urine. Metabolite classes included acylcarnitines, amino acids, biogenic amines, hexoses, phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins. From among 186 metabolites, 31 were detected in all CSF samples and 135 were detected in all plasma samples. A principal component analysis indicated that certain metabolites were differentially altered in trimethyl tin (TMT) treated groups when compared to controls. This was especially true in the CSF. Analysis of metabolite fold changes in the CSF indicated increases in acylcarnitines and phosphatidylcholines at 2 and 6 days, with increases in amino acids observed as long as 14 days after treatment. These changes suggest alterations in energy metabolism and mitochondrial and membrane damage in the central nervous system. In the plasma, there were increased levels of acylcarnitines, phosphatidyl- and lyso-phosphatidylcholines, amino acids, and sphingomyelins at 2 and 6 days. Additionally, the increased levels of acylcarnitines in urine at 2 and 6 days were most similar to the changes in metabolites noted in CSF and plasma. Our data provide evidence of significant changes in energy metabolism and mitochondrial and membrane damage in CNS, which were reflected in a peripheral fluid. Should it be demonstrated that plasma and urine markers mirror CSF markers and track aspects of CNS damage as evidenced by frank neuropathology (cell death), they may serve as useful, readily accessible surrogates of neurotoxicity. This is an abstract of a proposed presentation, and does not represent Agency policy.