| 著者 |
Hyun M, Rathor L, Kim HJ, Lee HJ, McElroy T, Ji M, Choi MS, Beck S, Bailey J, Kim HH, Sheng Y, Heo JD, Wohlgemuth S, Xiao R, Kim GS, Paik MJ, Kim YH, Kim SH, Lee MH, Han SM.
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| Abstract |
The synthetic antioxidant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6-PPD) is widely used in rubber products, but its toxicity in non-aquatic animals remains poorly understood. We investigated 6-PPD toxicity in mouse embryonic fibroblasts (MEFs) and Caenorhabditis elegans (C. elegans). In MEFs, 6-PPD caused dose-dependent increases in cell death, apoptosis, and mitochondrial dysfunction, along with elevated reactive oxygen species (ROS). In C. elegans, 6-PPD exposure led to higher mortality, delayed development, reduced reproduction, and shortened lifespan. Mitochondrial impairment, increased ROS, decreased mobility, and weakened stress tolerance were also observed. High-performance liquid chromatography (HPLC) analysis detected trace amounts of 6-PPD in C. elegans, whereas 6-PPD Quinone (6-PPDQ) was not detected within the analytical range. Furthermore, we found that 6-PPD upregulated the conserved transcription factor skinhead-1 (SKN-1/Nrf2) transcription factor. While SKN-1 was necessary for the reduced lifespan and early mortality caused by 6-PPD exposure, its loss failed to prevent the mitochondrial defects induced by 6-PPD exposure. Notably, SKN-1 gain-of-function mutations under basal conditions impaired mitochondrial function, and 6-PPD exposure further exacerbated these defects. These findings indicate that 6-PPD disrupts mitochondria through both SKN-1-dependent and SKN-1-independent mechanisms. Overall, our study demonstrates that 6-PPD impairs development, reproduction, healthspan, and lifespan through the SKN-1/Nrf2 pathway, with mitochondrial dysfunction mediated by both SKN-1/Nrf2-dependent and independent mechanisms.
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