Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu, China.
Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China.
Ecotoxicol Environ Saf. 2023 Dec;268:115685. doi: 10.1016/j.ecoenv.2023.115685. Epub 2023 Nov 16.
Triphenyl phosphate (TPHP), one widely used organophosphate flame retardant, has attracted accumulating attention due to its high detection rate in human biological samples. Up to date, the effects of TPHP exposure on intestinal health remain unexplored. In this study, BALB/c mice were used as a model and exposed to TPHP at dose of 2, 10, or 50 mg/kg body weight for 28 days. We observed Crohn's disease-like features in ileum and ulcerative colitis disease-like features in colon, such as shorter colon length, ileum/colon structure impairment, intestinal epithelial cell apoptosis, enrichment of proinflammatory cytokines and immune cells, and disruption of tight junction. Furthermore, we found that TPHP induced production of reactive oxygen species and apoptosis in intestinal epithelial Caco-2 cells, accompanied by disruption of tight junction between cells. To understand the molecular mechanism underlying TPHP-induced changes in intestines, we build the adverse outcome pathway (AOP) framework based on Comparative Toxicogenomics and GeneCards database. The AOP framework revealed that PI3K/AKT and FoxO signaling pathway might be associated with cellular apoptosis, an increase in ROS production, and increased inflammation response in mouse ileum and colon tissues challenged with TPHP. These results identified that TPHP induced IBD-like features and provided new perspectives for toxicity evaluation of TPHP.
磷酸三苯酯（TPHP）是一种广泛使用的有机磷阻燃剂，由于在人体生物样本中的高检出率而受到越来越多的关注。迄今为止，TPHP 暴露对肠道健康的影响仍未得到探索。在这项研究中，我们使用 BALB/c 小鼠作为模型，以 2、10 或 50mg/kg 体重的剂量暴露于 TPHP 28 天。我们观察到 TPHP 在回肠中引起了类似克罗恩病的特征，在结肠中引起了溃疡性结肠炎样的特征，如结肠长度缩短、回肠/结肠结构损伤、肠上皮细胞凋亡、促炎细胞因子和免疫细胞的富集以及紧密连接的破坏。此外，我们发现 TPHP 诱导了肠道上皮细胞 Caco-2 细胞中活性氧物质的产生和凋亡，同时伴有细胞间紧密连接的破坏。为了了解 TPHP 引起肠道变化的分子机制，我们基于比较毒理学基因组学和基因卡片数据库构建了不良结局途径（AOP）框架。AOP 框架表明，PI3K/AKT 和 FoxO 信号通路可能与细胞凋亡、ROS 产生增加以及 TPHP 处理的小鼠回肠和结肠组织中炎症反应增加有关。这些结果表明 TPHP 诱导了 IBD 样特征，并为 TPHP 的毒性评估提供了新的视角。
