Subchronic arsenism-induced oxidative stress and inflammation contribute to apoptosis through mitochondrial and death receptor dependent pathways in chicken immune organs.

Hongjing Zhao,Siwen Li,Yizhi Shao,Yu Wang,Zhijun Hou,Xiao Sun,Mingwei Xing,Ying He

doi:10.18632/oncotarget.16960

Abstract

In many organ dysfunctions, arsenic and its compounds are well known to induce apoptosis by the mitochondria and death receptor apoptotic pathways in liver and airway. However, it is less reported that which signaling pathways contribute to excessive apoptosis of chicken immune organs, a major target of toxic metals biotransformation, which suffer from subchronic arsenism. In this study, we investigated whether the mitochondria or death receptor apoptotic pathways activated in the immune organs (spleen, thymus and bursa of Fabricius) of one-day-old male Hy-line chickens exposed to arsenic trioxide (As2O3), which were fed on diets supplemented with 0, 0.625, 1.25 and 2.5 mg/kg BW of As2O3 for 30, 60 and 90 days. We found that (1) Oxidative damage and inflammatory response were confirmed in the immune organs of chickens fed on As2O3 diet. (2) Subchronic arsenism induced typical apoptotic changes in ultrastructure. (3) TdT-mediated dUTP Nick-End Labeling (TUNEL) showed that the number of apoptotic cells significantly increased under subchronic arsenism. (4) As2O3-induced apoptosis of immune organs involved in mitochondrial pathway (decrease of B-cell lymphoma-2 (Bcl-2) and increase of protein 53 (p53), Bcl-2 Associated X Protein (Bax), caspase-9, caspase-3) and death receptor pathway (increase of factor associated suicide (Fas) and caspase-8). In conclusion, this work is the first to demonstrate that the activation of mitochondria and death receptor apoptosis pathways can lead to excessive apoptosis in immune organs of chickens, which suffer from subchronic arsenism, meanwhile, oxidative stress as well as subsequent inflammatory is a crucial driver of apoptosis.

Highlights

In nature, arsenic is found among oxides and sulphur compounds, and mainly distributed through the environment by water cycling
We investigated whether the mitochondria or death receptor apoptotic pathways activated in the immune organs of one-dayold male Hy-line chickens exposed to arsenic trioxide (As2O3), which were fed on diets supplemented with 0, 0.625, 1.25 and 2.5 mg/kg body weight (BW) of As2O3 for 30, 60 and 90 days
This work is the first to demonstrate that the activation of mitochondria and death receptor apoptosis pathways can lead to excessive apoptosis in immune organs of chickens, which suffer from subchronic arsenism, oxidative stress as well as subsequent inflammatory is a crucial driver of apoptosis

Summary

Introduction

Arsenic is found among oxides and sulphur compounds, and mainly distributed through the environment by water cycling. Gaworecki et al [5] have reported that 25 ppm arsenicexposed killifish during embryogenesis could initiate molecular changes that appeared to lead to aberrant muscle www.impactjournals.com/oncotarget formation. For another in rats, As2O3 at a level of 5 mg/ kg body weight (BW)/day elevated the levels of caspase-3 and nitric oxide and increased the expression of nucleic factor κB (NF-κB) p65 in the liver [6], which indicated the symptom of intoxication. Our studies have shown that subchronic exposure to As2O3 in excess of 0.625 mg/kg BW causes inflammation, oxidative stress and heat shock response in the liver [11], brain [12] and immune organs [13]. Based on the abovementioned reports, arsenic and arsenic compounds toxic effects on health of animals and human beings, as well as their contamination in food and water have been a big problem in the environmental safety and public health

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