Ochratoxin A induced early hepatotoxicity: new mechanistic insights from microRNA, mRNA and proteomic profiling studies

Abstract

The mycotoxin ochratoxin A (OTA) is found widely in agricultural commodities. OTA can induce various toxicities. In this study, rats were gavaged with OTA for different weeks. Then, the expression of microRNAs, mRNAs and proteins were measured in the rat livers treated with OTA for 13 weeks. Our sequencing data suggests that the medial and the high doses of OTA exert different effects on livers. Five distinctive pathways were induced after OTA treatment as collectively demonstrated at miRNA, mRNA and protein levels. Two (primary bile acid biosynthesis, and metabolism of xenobiotics by cytochrome P450) are directly associated with liver damage, whereas the remaining pathways (arginine and proline metabolism, cysteine and methionine metabolism, and PPAR signaling pathway) cause metabolic disease. This study reveals OTA-induced early hepatotoxicity for the first time by combining multi-omics methods. The novel metabolic pathways may contribute to the pathogenesis of metabolic diseases later in life.O chratoxin A (OTA) is a low molecular weight mycotoxin produced by certain strains of filamentous fungi of the Aspergillus and Penicillium genera and has been detected in a large variety of agricultural commodities. OTA carries potential health-associated risks and has been classified as a possible human carcinogen (group 2B) by the International Agency for Research on Cancer 1 . OTA has previously been found to induce various toxic effects including nephrotoxicity, hepatotoxicity, immunotoxicity, genotoxicity, carcinogenicity, teratogenicity, neurotoxicity and mutagenicity.The liver is one of the major target organs of OTA biotransformation. Although, some early hepatotoxicity studies employed relative high concentrations of OTA and found remarkable liver lesion 2,3 , lower doses of OTA did not provoke significant pathological changes 4-6 . Most of the previous studies have been extensively focused on OTA-induced kidney damage, less on liver. However, it is still unknown how OTA affects the liver which is the largest detoxification organ of body. Therefore, the identification of early hepatotoxicity can be helpful to understand the mechanism of some diseases that may be developed and progressed by OTA in later stage, and to prevent these diseases in early stage to improve human health.Omics approaches, such as transcriptome and proteome, are promising to detect the pathological changes of liver at a molecular level. Till date, omics technology has been employed only in a few studies to understand the mechanism of OTA hepatotoxicity. Moreover, a high-throughput microarray profiling study on HepG2 liver cell transcriptome demonstrated that multiple hepatic metabolism genes are modulated by OTA exposure 7 . In addition, proteomic approaches have helped identify key proteins in the livers of pigs treated with OTA 8 . These omics approaches have widened our view about OTA hepatotoxicity, however the mechanism of OTA actions remains largely unknown.Recently, microRNAs (miRNAs) in animals and plants are shown to play an impor...

Limited Link between Oxidative Stress and Ochratoxin A—Induced Renal Injury in an Acute Toxicity Rat Model

“…OTA displays nephrotoxicity [4], hepatotoxicity [1], carcinogenicity [5], and neurotoxicity [6] in mammals. There are some studies that have revealed the mechanisms of OTA, such as, protein synthesis inhibition [7], lipid peroxidation [8], mitochondrial function inhibition [9], DNA methylation [10], miRNA regulation [11], the changes of enteric microorganism [12], renal cortex fibrosis, and epithelial-to-mesenchymal transition [13,14] etc. Some researchers also suggested that the toxicity is related to oxidative stress, and other researchers insist that DNA damage, including DNA adduct formation and DNA strand breaks, are responsible [15,16,17].…”

Toxicity study of ochratoxin A using HEK293 and HepG2 cell lines based on microRNA profiling

“…44 In addition, pathways related to cellular processes were more common in the kidney, 16 while pathways related to organismal systems were more common in the liver. 48 Most of the enriched pathways are overlapped after classification; most pathways are related to human cancer and signal transduction. Previous research also showed the similarity of pathways in different systems.…”

“…The in vivo experiment found that MAPK pathway is critical in nephrotoxicity induced by OTA in rats. As our preliminary research have described the toxicological mechanism of OTA-induced nephrotoxicity and hepatoxicity in rats via miRNA profiling 47,48 (Supplementary Tables 1 and 2), we want to further study how OTA affects human cell lines. The comparative analysis of the regulated miRNAs, the classification of regulated pathways, and the comparison of the damage to miRNA processing are novel in this in vitro study.…”

Prevalence of Ochratoxigenic Fungi and Ochratoxin A Residues in Animal Feeds and Modulation of Their Toxic Effects by Glutathione

“…Theses decreased in values might be due to OTA-induced damage to liver (Qi et al, 2014). Proteinuria especially albuminuria resulting from toxic damage to nephrons could have resulted in decreased albumin fraction observed in the study by Gupta et al, (2009).…”