Oncotarget

Research Papers:

Induction of mitochondria-mediated apoptosis and PI3K/Akt/ mTOR-mediated autophagy by aflatoxin B2 in hepatocytes of broilers

Binlong Chen, Diyan Li, Miao Li, Sichen Li, Kenan Peng, Xian Shi, Lanyun Zhou, Pu Zhang, Zhongxian Xu, Huadong Yin, Yan Wang, Xiaoling Zhao and Qing Zhu _

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Oncotarget. 2016; 7:84989-84998. https://doi.org/10.18632/oncotarget.13356

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Abstract

Binlong Chen1,*, Diyan Li1,*, Miao Li1, Sichen Li1, Kenan Peng1, Xian Shi1, Lanyun Zhou1, Pu Zhang1, Zhongxian Xu1, Huadong Yin1, Yan Wang1, Xiaoling Zhao1, Qing Zhu1

1Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, P.R.China, 611130

*These authors contribute equally to this work

Correspondence to:

Qing Zhu, email: zhuqing@sicau.edu.cn

Keywords: aflatoxin B2, mitochondria-mediated apoptosis, PI3K/Akt/mTOR-mediated autophagy, hepatocytes, broiler

Received: May 18, 2016     Accepted: October 26, 2016     Published: November 15, 2016

ABSTRACT

Aflatoxins have been shown to induce hepatotoxicity in animal models, but the effects of aflatoxin B2 (AFB2) on broiler hepatocytes is unclear. This study aimed to investigate the effects of AFB2 on apoptosis and autophagy to provide an experimental basis for understanding the mechanism of aflatoxin-induced hepatotoxicity. One hundred-twenty Cobb500 broilers were allocated to four groups and exposed to 0 mg/kg, 0.2 mg/kg, 0.4 mg/kg, and 0.8 mg/kg of AFB2 per day for 21 d. AFB2 exerted potent proapoptotic and proautophagic effects on hepatocytes, with increased numbers of apoptotic and autophagic hepatocytes.

Poly ADP-ribose polymerase (PARP) was cleaved and caspase-3 was activated in experimental groups, showing that the apoptosis of hepatocytes was triggered by AFB2. Increased levels of the autophagy factors Beclin-1 and LC3-II/LC3-I, as well as down-regulation of p62, a marker of autophagic flux, provided additional evidence for AFB2-triggered autophagy. AFB2 induced mitochondria-mediated apoptosis via the production of reactive oxygen species (ROS) and promotion of the translocation of Bax and cytochrome c (cyt c) between mitochondria and the cytosol, triggering the formation of apoptosomes. AFB2 also inhibited the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway by activating PI3K, Akt, and mTOR and inhibiting their phosphorylation, contributing to the proautophagic activity of AFB2. These findings provide new insights into the mechanisms involved in AFB2-induced hepatotoxicity in broilers.


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