Iron overload by Superparamagnetic Iron Oxide Nanoparticles is a High Risk Factor in Cirrhosis by a Systems Toxicology Assessment

Fang Yang,Hang Xie,Mengzhu Zhao,Yushuang Wei,Yang Mao,Qibing Zhou

doi:10.1038/srep29110

Abstract

Superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent have been widely used in magnetic resonance imaging for tumor diagnosis and theranostics. However, there has been safety concern of SPIONs with cirrhosis related to excess iron-induced oxidative stress. In this study, the impact of iron overload by SPIONs was assessed on a mouse cirrhosis model. A single dose of SPION injection at 0.5 or 5 mg Fe/kg in the cirrhosis group induced a septic shock response at 24 h with elevated serum levels of liver and kidney function markers and extended impacts over 14 days including high levels of serum cholesterols and persistent low serum iron level. In contrast, full restoration of liver functions was found in the normal group with the same dosages over time. Analysis with PCR array of the toxicity pathways revealed the high dose of SPIONs induced significant expression changes of a distinct subset of genes in the cirrhosis liver. All these results suggested that excess iron of the high dose of SPIONs might be a risk factor for cirrhosis because of the marked impacts of elevated lipid metabolism, disruption of iron homeostasis and possibly, aggravated loss of liver functions.

Highlights

Systems toxicology is a new forging cross-disciplinary toxicology field that provides in-depth risk assessment of chemical entities in a biological system[18]
Upon injection of SPIONs at 5 mg Fe/kg, significant expression changes of a distinct set of genes in the immunotoxicity, oxidative stress and mitochondrial metabolism, lipid metabolism and cell death related pathways were induced in the liver tissue at 24 h
Since most of iron from the SPIONs was retained in the cirrhotic liver at 24 h post injection (Table 1), these toxicity consequences by SPIONs were consistent with responses to enhanced oxidative stress by the iron overload[8,10,11]

Summary

Introduction

Systems toxicology is a new forging cross-disciplinary toxicology field that provides in-depth risk assessment of chemical entities in a biological system[18]. The systems toxicology approach has demonstrated hepatotoxicants and tobacco smoke toxicants-induced gene expression for prediction of the toxicity risk[19,20]. Microarray analysis has been used in the systems toxicology to elucidate cytotoxic mechanisms of PPAR gamma agonist drugs[21,22]. A mouse cirrhosis model with the use of biocompatible SPIONs was assessed by the systems toxicity approach. The impact of biocompatible SPIONs in cirrhosis was first determined by serum biochemistry profiles post SPION injection over fourteen days. The effect of SPIONS on the regulation of 370 genes from more than thirteen molecular toxicity pathways in the liver tissue was assessed by RT2 PCR array. The overall toxicity assessment was achieved by the combination of these two approaches to reveal the underlying toxicity risk and mechanisms

Methods

Results

Conclusion