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J. Hazard. Mater., Available online 31 October 2025, 140332 | https://doi.org/10.1016/j.jhazmat.2025.140332 6-PPD induces mitochondrial dysfunction and reduces healthspan and lifespan through SKN-1 in Caenorhabditis elegans

Moonjung Hyun^1,#,* Laxmi Rathor^2,#, Hye-Jin Kim¹, Ho-Jeong Lee¹, Taylor McElroy², Moongi Ji³, Min-Seok Choi⁴, Steven Beck², Julia Bailey2, Hun Hwan Kim2,5, Yi Sheng2, Jeong-Doo Heo1, Stephanie Wohlgemuth2, Rui Xiao2, Gon Sup Kim5, Man-Jeong Paik3, Yong-Hyun Kim4, Sung-Hwan Kim6, Myon Hee Lee7,8,*, and Sung Min Han^2,9,*

¹Division of Gyeongnam Bio-Environmental Research, Bio-Health Research Center, Jinju, 52834, Republic of Korea
²Department of Physiology and Aging, College of Medicine, Institute on Aging, University of Florida, Gainesville, FL 32610, USA
³College of Pharmacy, Sunchon National University, Suncheon 57922, Republic of Korea
⁴Department of Environmental Engineering, Jeonbuk National University, Jeonju 54896, Republic of Korea
⁵College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea
⁶Division of Jeonbuk Advanced Bio Research, Korea Institute of Toxicology, Jeongeup, 56212, Republic of Korea
⁷Department of Internal Medicine, Hematology/Oncology Division, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA
⁸Department of Biology, East Carolina University, Greenville, NC 27858, USA
⁹Lead contact

^#These authors contributed equally
^*Corresponding authors

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, 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 6-PPD concentrations in C. elegans that were comparable to levels reported in the human body. 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

논문정보

형식Research article
게재일2025년 10월 (BRIC 등록일 2025-11-04)
연구진국내+국외 연구진
분야 생명과학 > 분류/생태/환경생물학

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