Key Laboratory of Pollution Processes and Environmental Criteria (Ministry of Education)/Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering, Nankai University, Tianjin, 300071, China.
Department of Digestion, General Hospital, Shenyang Military Command, Shenyang, 110016, China.
Environ Sci Pollut Res Int. 2019 Nov;26(32):33351-33362. doi: 10.1007/s11356-019-06383-5. Epub 2019 Sep 14.
As the application and environmental release of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) are being increased rapidly, serious concerns have been raised regarding its adverse effects on human health. Exposure to TDCIPP has been implicated in hepatotoxicity, but the molecular mechanisms remain unclear. Here, both male and female Sprague Dawley rats were administered TDCIPP with 125, 250, or 500 mg/kg/day for 12 weeks. Then the ultrastructure of liver, biochemical indicators in serum and liver, and hepatic gene expression were analyzed to reveal molecular mechanisms of hepatotoxicity induced by TDCIPP. Continuous TDCIPP exposure decreased body weight, particularly in 500 mg/kg/day TDCIPP-exposed males, and dose dependently increased the ratio of liver to body weight in both genders. The decreased levels of triglyceride, cholesterol, and transaminase in the serum and livers were observed in both genders after TDCIPP exposure, which indicated dysfunction in the hepatic metabolism. Liver histopathology revealed hepatocellular damages in males and females after TDCIPP exposure. The transcriptomic analysis indicated that TDCIPP exposure significantly changed pathways of bile acid metabolism, inflammatory response, oxidative phosphorylation and carcinogenicity in 250 and 500 mg/kg/day TDCIPP-exposed males and 500 mg/kg/day TDCIPP-exposed females, and there was no statistical significance in any other TDCIPP-exposed groups. The transcriptional analysis showed that TDCIPP exposure led to oxidative stress in the livers of rats, thereby increasing the inflammatory response and promoting mechanisms of carcinogenesis in both genders. Finally, TDCIPP led to more severe adverse phenotypic effects in male than female rats.
随着三（1,3-二氯-2-丙基）磷酸酯（TDCIPP）的应用和环境释放迅速增加，人们对其对人类健康的不良影响表示严重关切。接触 TDCIPP 与肝毒性有关，但分子机制尚不清楚。在这里，雄性和雌性 Sprague Dawley 大鼠分别以 125、250 或 500mg/kg/天的剂量接受 TDCIPP 处理 12 周。然后分析肝脏的超微结构、血清和肝脏中的生化指标以及肝基因表达，以揭示 TDCIPP 诱导肝毒性的分子机制。连续接触 TDCIPP 会降低体重，尤其是在 500mg/kg/天 TDCIPP 暴露的雄性大鼠中，并且在两性中都依赖于剂量增加肝重与体重的比值。血清和肝脏中甘油三酯、胆固醇和转氨酶水平的降低表明肝脏代谢功能障碍。TDCIPP 暴露后，雄性和雌性大鼠的肝脏组织病理学均显示肝细胞损伤。转录组分析表明，在 250 和 500mg/kg/天 TDCIPP 暴露的雄性和 500mg/kg/天 TDCIPP 暴露的雌性大鼠中，TDCIPP 暴露显著改变了胆汁酸代谢、炎症反应、氧化磷酸化和致癌作用的途径，而在任何其他 TDCIPP 暴露组中均无统计学意义。转录分析表明，TDCIPP 暴露导致大鼠肝脏氧化应激，从而增加炎症反应并促进两性致癌机制。最后，TDCIPP 导致雄性大鼠比雌性大鼠表现出更严重的不良表型效应。
