College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China.
State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products/Key Laboratory of Detection for Pesticide Residues and Control of Zhejiang, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China.
Sci Total Environ. 2023 Apr 15;869:161836. doi: 10.1016/j.scitotenv.2023.161836. Epub 2023 Jan 28.
N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) is a widely used additive for protecting various rubber products, and its product of oxidation N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPDQ) has attracted extensive attention in aquatic toxicity. However, the toxicity of 6PPD and 6PPDQ in mammals has not been reported yet. In this study, the effects of 6PPD and 6PPDQ on the liver of C57BL/6 mice were assessed by orally administering different doses of 6PPD and 6PPDQ (10, 30, and 100 mg/kg) in mice for 6 weeks. 6PPD and 6PPDQ were found to bioaccumulate in the liver in a dose-dependent manner. Moreover, a high dose of 6PPD and 6PPDQ exposure increased not only the liver weights but also liver triglyceride levels, indicating that 6PPD and 6PPDQ exposure induced hepatotoxicity in mice. Furthermore, transcriptomic analysis revealed that 6PPD and 6PPDQ induced differential expression of genes mainly enriched in glycolipid metabolism, immune-related, and glutathione metabolism pathways. Therefore, 6PPD and 6PPDQ altered hepatic metabolism in mice. Furthermore, 6PPDQ could induce an immune response by upregulating the transcription of immune-related genes and promoting macrophage infiltration in the liver. In conclusion, our study revealed the toxic effects of 6PPD and 6PPDQ exposure on multi-endpoints in the liver of mice and improve our understanding of the health risks of 6PPD and 6PPDQ to mammals. The findings of our study may help formulate better safety regulations for the use and disposal of rubber products.
N-(1,3-二甲基丁基)-N'-苯基对苯二胺（6PPD）是一种广泛用于保护各种橡胶制品的添加剂，其氧化产物 N-(1,3-二甲基丁基)-N'-苯基对苯二胺-醌（6PPDQ）在水生毒性方面引起了广泛关注。然而，6PPD 和 6PPDQ 在哺乳动物中的毒性尚未有报道。在这项研究中，通过给 C57BL/6 小鼠口服不同剂量的 6PPD 和 6PPDQ（10、30 和 100mg/kg）6 周，评估了 6PPD 和 6PPDQ 对小鼠肝脏的影响。结果发现，6PPD 和 6PPDQ 以剂量依赖的方式在肝脏中生物累积。此外，高剂量的 6PPD 和 6PPDQ 暴露不仅增加了肝脏重量，还增加了肝脏甘油三酯水平，表明 6PPD 和 6PPDQ 暴露诱导了小鼠的肝毒性。此外，转录组分析显示，6PPD 和 6PPDQ 诱导的基因表达差异主要富集在糖脂代谢、免疫相关和谷胱甘肽代谢途径中。因此，6PPD 和 6PPDQ 改变了小鼠的肝脏代谢。此外，6PPDQ 通过上调免疫相关基因的转录和促进巨噬细胞在肝脏中的浸润，诱导免疫反应。总之，本研究揭示了 6PPD 和 6PPDQ 暴露对小鼠肝脏多终点的毒性作用，提高了我们对 6PPD 和 6PPDQ 对哺乳动物健康风险的认识。我们的研究结果可能有助于制定更好的橡胶制品使用和处理安全法规。
