2-Amino-3-Methylimidazo[4,5-f]quinoline Triggering Liver Damage by Inhibiting Autophagy and Inducing Endoplasmic Reticulum Stress in Zebrafish (Danio rerio).

Dan Li,Bo Peng,Shuo Wang,Tianchang Zhang,Yan Zhang,Hongwen Sun,Zhi Li

doi:10.3390/toxins13110826

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Journal: Toxins	Publication Date: Nov 22, 2021
Citations: 5	License type: CC BY 4.0

Affiliation: Nankai University

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It is important to note that 2-Amino-3-methylimidazole[4,5-f]quinoline (IQ) is one of the most common heterocyclic amines (HCAs), which is a class of mutagenic/carcinogenic harmful compounds mainly found in high-protein thermal processed foods and contaminated environments. However, the pre-carcinogenic toxicity of IQ to the liver and its mechanism are poorly understood, further research is needed. In light of this, we exposed zebrafish to IQ (0, 8, 80, and 800 ng/mL) for 35 days, followed by comprehensive experimental studies. Histopathological and ultrastructural analysis showed that hepatocytes were damaged. TUNEL results showed that IQ induced apoptosis of liver cells, the expression of apoptosis factor gene was significantly increased, and the expression of Bcl-2 protein was significantly decreased. In addition, upregulated expression of the 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) and endoplasmic reticulum stress (ERS)-related factors transcription levels were elevated obviously, suggesting that IQ induced ERS. Decreased protein expression of autophagy-related 5 (Atg5)-Atg12, Beclin1, and LC3-II, increased protein expression of p62, and autophagy-related factors transcription levels were significantly decreased, suggesting that IQ inhibited autophagy. Overall, our research showed that the potential harm of IQ to the liver before the occurrence of liver cancer was related to ERS and its mediated autophagy and apoptosis pathways.

Highlights

Introduction iationsHeterocyclic amines (HCAs), a family of mutagenic/carcinogenic compounds, are mainly generated during the pyrolysis of creatine, amino acids and proteins [1]
We focused on the roles of autophagy and apoptosis via endoplasmic reticulum stress (ERS) in liver damage because the crosstalk of their pathways plays a critical role in liver damage [21,22,24], and because their relationship in the liver is still not clear
To verify the alterations in autophagic response, we investigated whether the functhe function of autophagy was impaired in zebrafish livers after IQ exposure through tion of autophagy was impaired in zebrafish livers after IQ exposure through analyzing analyzing autophagy-related genes and proteins

Summary

Introduction

Heterocyclic amines (HCAs), a family of mutagenic/carcinogenic compounds, are mainly generated during the pyrolysis of creatine, amino acids and proteins [1]. HCAs exist extensively in the environment, such as high-protein thermally processed foods, cigarette smoke, polluted river water, the atmosphere, soil, etc. It is important to note that 2-Amino-3-methylimidazole[4,5-f]quinoline (IQ) is one of the most studied HCAs because of its highly carcinogenic and genotoxic nature [3]. Agency for Research on Cancer (IARC) classified IQ as “probably carcinogenic to humans”. (group 2A carcinogens) [2]. The classification, exposure pathway, existence form, and mutagenic/carcinogenic mechanism of HCAs have been extensively studied in the early stage, but so far, the scientific research system for these issues is not complete [4,5].

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