6-PPD-quinone is an agonist of cannabinoid receptor 2 (CNR2) and exhibits high affinity for CNR2[1]. 6-PPD-quinone is a product generated by the reaction of 6-PPD with O3 and is recognized as an emerging environmental pollutant[2]. 6-PPD-quinone is toxic not only to aquatic species and mammals, but also damages human health, causing a variety of adverse effects such as hepatotoxicity, enterotoxicity, pulmonary toxicity and neurotoxicity[3].
In vitro, RTL-W1 and RTgill-W1 cells were treated with 6-PPD-quinone (0–80μg/L) for 24 hours. RTL-W1 cells showed insensitivity to 6-PPD-quinone, while RTgill-W1 cells exhibited significantly decreased cell viability at 80μg/L, and at 20μg/L, the oxygen consumption rate was doubled by uncoupling the mitochondrial electron transport chain[4]. When Ishikawa cells were treated with 6-PPD-quinone (1–100nM) for 96 hours, it stimulated endometrial cell proliferation through the ERα/GPER signaling pathway and promoted endometrial cell migration via ERα/GPER-regulated epithelial-mesenchymal transition and inflammatory responses[5].
In vivo, intraperitoneal injection of mice with 6-PPD-quinone (0.4mg/kg, 4mg/kg) for 28 days induced inflammatory responses and caused chronic damage to multiple organs, including abnormal liver and kidney function, lung injury, and toxicity to the reproductive and nervous systems, with toxicity worsening as the dose increased[6]. When 6-PPD-quinone (0-10μg/L) was applied to Caenorhabditis elegans, it significantly reduced reproductive capacity, exacerbated germ cell apoptosis and DNA damage, and was accompanied by high expression of related genes such as cep-1, clk-2, hus-1, and mrt-2[7].
References:
[1] Yang Y, Sun N, Lv J, et al. Environmentally realistic dose of tire-derived metabolite 6PPD-Q exposure causes intestinal jejunum and ileum damage in mice via cannabinoid receptor-activated inflammation. Sci Total Environ 2024, 918:170679.
[2] Hua X, Wang D Tire-rubber related pollutant 6-PPD quinone: A review of its transformation, environmental distribution, bioavailability, and toxicity. J Hazard Mater 2023, 459:132265.
[3] Wan X, Liang G, Wang D Potential human health risk of the emerging environmental contaminant 6-PPD quinone. Sci Total Environ 2024, 949:175057.
[4] Mahoney H, da Silva Junior FC, Roberts C, et al. Exposure to the Tire Rubber-Derived Contaminant 6PPD-Quinone Causes Mitochondrial Dysfunction In Vitro. Environmental Science & Technology Letters 2022, 9(9):765-771.
[5] Tang L, Li X, Zhu S-Y, et al. 6PPD and 6PPD Quinone Induce Endometrial Cell Dysfunction via Activating ERα and GPER at Human-Relevant Levels. Environmental Science & Technology 2025, 59(20):9918-9929.
[6] He W, Gu A, Wang D Four-week repeated exposure to tire-derived 6-PPD quinone causes multiple organ injury in male BALB/c mice. Science of The Total Environment 2023, 894:164842.
[7] Hua X, Feng X, Liang G, et al. Long-term exposure to 6-PPD quinone reduces reproductive capacity by enhancing germline apoptosis associated with activation of both DNA damage and cell corpse engulfment in Caenorhabditis elegans. Journal of Hazardous Materials 2023, 454:131495.
6-PPD-quinone是大麻素受体2（CNR2）的激动剂，对CNR2具有高亲和力。6-PPD-quinone是由6-PPD与O3反应生成的产物, 被公认为一种新兴的环境污染物[2]。6-PPD-quinone不仅对水生物种和哺乳动物有毒性，还会损害人类健康，引发肝毒性、肠毒性、肺毒性和神经毒性等多种不良影响[3]。
在体外，6-PPD-quinone（0-80μg/L）分别处理RTL-W1和RTgill-W1细胞24小时，RTL-W1细胞对 6-PPD-quinone不敏感，而RTgill-W1细胞在80μg/L时细胞活力显著下降，且在20μg/L浓度时通过解偶联线粒体电子传递链使耗氧率提高两倍 [4]。使用6-PPD-quinone（1-100nM）处理Ishikawa细胞96h，通过ERα/GPER信号通路刺激子宫内膜细胞增殖, 并通过ERα/GPER调节的上皮间质转化和炎症反应促进子宫内膜细胞迁移 [5]。
在体内，6-PPD-quinone（0.4mg/kg、4mg/kg）通过腹腔注射小鼠28天，可诱导炎症反应并导致多器官慢性损伤，包括肝肾功能异常、肺损伤、生殖系统和神经系统毒性，且毒性随剂量增加而加重[6]。6-PPD-quinone（0-10μg/L）作用于秀丽隐杆线虫，能够显著降低其繁殖能力，加剧生殖细胞凋亡和DNA损伤，并伴随着cep-1、clk-2、hus-1和mrt-2等相关基因的高表达[7]。