Mughal Muhammad Jameel, Xi Peng, Yi Zhou, Jing Fang
Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, PR China.
Key Laboratory of Southwest China Wildlife Resources Conservation (Ministry of Education), College of Life Sciences, China West Normal University, Nanchong, Sichuan, China.
Oncotarget. 2017 Jan 31;8(5):8239-8249. doi: 10.18632/oncotarget.14158.
The fungal metabolites produced by Aspergillus flavus and Aspergillus parasiticus cause detrimental health effects on humans and animals. Particularly aflatoxin B1 (AFB1) is the most studied and a well-known global carcinogen, producing hepatotoxic, genotoxic and immunotoxic effects in multiple species. AFB1 is shown to provoke liver dysfunctioning by causing hepatocytes apoptosis and disturbing cellular enzymatic activities. In liver, AFB1 causes apoptosis via extrinsic mechanism because of high expression of death receptor pathway. The detailed mechanism of AFB1 induced hepatocytes apoptosis, via death receptor pathway still remains elusive. So the present study was conducted to explore apoptotic mechanism initiated by death receptors and associated genes in aflatoxin B1 induced liver apoptosis in chickens fed with AFB1 for 3 weeks. Results from the present study displayed histopathological and ultrastructural changes in liver such as hydropic degeneration, fatty vacuolar degeneration and proliferation of bile duct in hepatocytes in AFB1 group, along with imbalance between reactive oxygen species (ROS) and antioxidant defense system upon AFB1 ingestion. Moreover, AFB1 intoxicated chickens showed upregulation of death receptors FAS, TNFR1 and associated genes and downregulation of inhibitory apoptotic proteins XIAP and BCL-2. The results obtained from this novel and comprehensive study including histopathological, ultrastructural, flow cytometrical and death receptor pathway gene expression profiles, will facilitate better understanding of mechanisms and involvement of death receptor pathway in hepatocytes apoptosis induced by AFB1 and ultimately may be helpful in bringing down the toxigenic potential of AFB1.
黄曲霉和寄生曲霉产生的真菌代谢产物会对人类和动物的健康产生有害影响。特别是黄曲霉毒素B1（AFB1）是研究最多且广为人知的全球致癌物，对多种物种具有肝毒性、遗传毒性和免疫毒性作用。AFB1通过引起肝细胞凋亡和干扰细胞酶活性，导致肝功能失调。在肝脏中，由于死亡受体途径的高表达，AFB1通过外在机制导致细胞凋亡。AFB1通过死亡受体途径诱导肝细胞凋亡的详细机制仍然不清楚。因此，本研究旨在探讨在给鸡喂食AFB1 3周后，AFB1诱导肝脏细胞凋亡过程中，由死亡受体和相关基因引发的凋亡机制。本研究结果显示，AFB1组肝脏出现组织病理学和超微结构变化，如肝细胞出现水样变性、脂肪空泡变性和胆管增生，同时摄入AFB1后活性氧（ROS）与抗氧化防御系统之间失衡。此外，AFB1中毒的鸡表现出死亡受体FAS、TNFR1及相关基因上调，以及凋亡抑制蛋白XIAP和BCL-2下调。这项新颖且全面的研究结果包括组织病理学、超微结构、流式细胞术和死亡受体途径基因表达谱，将有助于更好地理解AFB1诱导肝细胞凋亡过程中死亡受体途径的机制及参与情况，最终可能有助于降低AFB1的产毒潜力。
