<br>环境现实剂量的轮胎衍生代谢物 6PPD-Q 暴露通过大麻素受体激活的炎症导致小鼠肠道空肠和回肠损伤,Science of the Total Environment

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环境现实剂量的轮胎衍生代谢物 6PPD-Q 暴露通过大麻素受体激活的炎症导致小鼠肠道空肠和回肠损伤
Science of the Total Environment ( IF 8.2 ) Pub Date : 2024-02-05 , DOI: 10.1016/j.scitotenv.2024.170679
Yan Yang ₁ , Nan Sun ₂ , Jia Lv ₂ , Haojia Chen ₁ , Hongqian Wang ₃ , Jingjing Xu ₂ , Jiayue Hu ₄ , Lin Tao ₂ , Mingliang Fang ₅ , Yichao Huang ₂

Affiliation

-(1,3-二甲基丁基)-'-苯基-苯二胺醌 (6PPD-Q) 是常见轮胎添加剂 6PPD 的醌衍生物，其在环境和人体（包括成人、孕妇）中的存在已被广泛报道。妇女和儿童。然而，关于 6PPD-Q 在环境相关剂量下对哺乳动物的潜在肠道毒性的了解仍然未知。在本研究中，通过口服环境相关剂量或较低水平的 6PPD-Q（0.1、1、10 和 100 μg/kg）21 天来评估 6PPD-Q 对成年 ICR 小鼠肠道的影响。我们发现 6PPD-Q 以剂量依赖性方式破坏肠道屏障的完整性，主要是在空肠和回肠，但不在十二指肠或结肠中。此外，肠道炎症表现为 TNF-α、IL-1 和 IL-6 水平升高，主要在 10 和 100 μg/kg 剂量下观察到。使用反向目标筛选技术结合分子动力学模拟模型，我们确定了关键的大麻素受体，包括 CNR2 激活，可能介导 6PPD-Q 诱导的肠道炎症。总之，这项研究为新兴污染物 6PPD-Q 对哺乳动物肠道的毒性作用提供了新的见解，并且该化学物质可能是调节炎症的大麻素受体激动剂。

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Environmentally realistic dose of tire-derived metabolite 6PPD-Q exposure causes intestinal jejunum and ileum damage in mice via cannabinoid receptor-activated inflammation

-(1,3-dimethylbutyl)-′-phenyl--phenylenediamine quinone (6PPD-Q) is a quinone derivative of a common tire additive 6PPD, whose occurrence has been widely reported both in the environment and human bodies including in adults, pregnant women and children. Yet, knowledge on the potential intestinal toxicity of 6PPD-Q in mammals at environmentally relevant dose remain unknown. In this study, the effects of 6PPD-Q on the intestines of adult ICR mice were evaluated by orally administering environmentally relevant dose or lower levels of 6PPD-Q (0.1, 1, 10, and 100 μg/kg) for 21 days. We found that 6PPD-Q disrupted the integrity of the intestinal barrier, mostly in the jejunum and ileum, but not in the duodenum or colon, in a dose-dependent manner. Moreover, intestinal inflammation manifested with elevated levels of TNF-α, IL-1, and IL-6 mostly observed in doses at 10 and 100 μg/kg. Using reverse target screening technology combining molecular dynamic simulation modeling we identified key cannabinoid receptors including CNR2 activation to be potentially mediating the intestinal inflammation induced by 6PPD-Q. In summary, this study provides novel insights into the toxic effects of emerging contaminant 6PPD-Q on mammalian intestines and that the chemical may be a cannabinoid receptor agonist to modulate inflammation.

更新日期：2024-02-05

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