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Mitochondrial DNA damage as a peripheral biomarker for mitochondrial toxin exposure in rats.

Research paper by Laurie H LH Sanders, Evan H EH Howlett, Jennifer J McCoy, J Timothy JT Greenamyre

Indexed on: 23 Sep '14Published on: 23 Sep '14Published in: Toxicological sciences : an official journal of the Society of Toxicology



Abstract

Demonstrating or verifying a current or past exposure to an environmental mitochondrial toxin or toxicant is extraordinarily difficult. Thus, there is a pressing need to develop a biomarker for exposure to environmental mitochondrial inhibitors. Rotenone, an environmental toxicant, is a potent inhibitor of the mitochondrial electron transfer chain. Rotenone specifically inhibits complex I throughout the body and brain, thereby producing systemic mitochondrial impairment. As such, rotenone is a prototypical clinically relevant, environmental mitochondrial toxicant that may be used as an ideal initial platform to develop accessible biomarkers of exposure. The over-arching goal of this work is to explore and validate peripheral (blood and skeletal muscle) DNA damage as a biomarker of mitochondrial toxicant exposure using the rat rotenone model. In this effort, we utilized an extremely sensitive quantitative polymerase chain reaction (QPCR)-based assay that simultaneously allows the assessment of multiple forms of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage. We found mtDNA damage in blood is detected after subclinical rotenone exposure and the damage persists even after complex I activity has returned to normal. With a more sustained rotenone exposure, mtDNA damage is also detected in skeletal muscle, suggesting that mtDNA damage in this tissue simply lags behind blood. Using the QPCR-based assay, we have no evidence for nDNA damage in peripheral tissues after rotenone exposure either acutely or chronically. Overall, these data support the idea that mtDNA damage in peripheral tissues in the rotenone model may provide a biomarker of past or ongoing mitochondrial toxin exposure.

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