A Toxicogenomics Approach to Identify New Plausible Epigenetic Mechanisms of Ochratoxin A Carcinogenicity in Rat

Abstract

Ochratoxin A (OTA) is a mycotoxin occurring naturally in a wide range of food commodities. In animals, it has been shown to cause a variety of adverse effects, nephrocarcinogenicity being the most prominent. Because of its high toxic potency and the continuous exposure of the human population, OTA has raised public health concerns. There is significant debate on how to use the rat carcinogenicity data to assess the potential risk to humans. In this context, the question of the mechanism of action of OTA appears of key importance and was studied through the application of a toxicogenomics approach. Male Fischer rats were fed OTA for up to 2 years. Renal tumors were discovered during the last 6 months of the study. The total tumor incidence reached 25% at the end of the study. Gene expression profile was analyzed in groups of animals taken in intervals from 7 days to 12 months. Tissue-specific responses were observed in kidney versus liver. For selected genes, microarray data were confirmed at both mRNA and protein levels. In kidney, several genes known as markers of kidney injury and cell regeneration were significantly modulated by OTA. The expression of genes known to be involved in DNA synthesis and repair, or genes induced as a result of DNA damage, was only marginally modulated. Very little or no effect was found amongst genes associated with apoptosis. Alterations of gene expression indicating effects on calcium homeostasis and a disruption of pathways regulated by the transcription factors hepatocyte nuclear factor 4 alpha (HNF4alpha) and nuclear factor-erythroid 2-related factor 2 (Nrf2) were observed in the kidney but not in the liver. Previous data have suggested that a reduction in HNF4alpha may be associated with nephrocarcinogenicity. Many Nrf2-regulated genes are involved in chemical detoxication and antioxidant defense. The depletion of these genes is likely to impair the defense potential of the cells, resulting in chronic elevation of oxidative stress in the kidney. The inhibition of defense mechanism appears as a highly plausible new mechanism, which could contribute to OTA carcinogenicity.

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

“…The authors also observed that circadian exercise, cholesterol biosynthesis and lipid metabolism were influenced in the rat liver which is similar with our high dose group 30 . In another study with 300 ml OTA/kg bw, similar dose in our study, carbon metabolism, amino acid metabolism were influenced in the liver 31 . This comparative analysis suggests that a high-dose of OTA influences not only the basic metabolism but also endocrine environment, leading to the imbalance of whole body, while, a low-dose of OTA enables the imbalance of energy metabolism, but the detoxification of the liver still functions.…”

“…We compared the miRNA pathways with at least two and three algorithms, and found that the lost pathways with at least three algorithms mainly concentrated on amino acid metabolism, carbohydrate metabolism, glycan biosynthesis, lipid metabolism, and metabolism of cofactors and vitamins. In previous studies on OTA, amino acid metabolism, carbon metabolism pathways were influenced in the liver 31 . In addition, genes related with glycan biosynthesis in HepG2 cells are changed in response to OTA treatment 7 .…”

“…Male Tsc2 EKER rats gavaged with OTA also changed their energy provision 43 . In addition, liver lipid metobolism was down-regulated of male F344 rats after OTA treatments in several studies 30,31 . In our result, the protein (such as Hmgcs2) was down-regulated in PPAR pathway, which is the major regulator of lipid and fatty acid metabolism.…”

Genotoxicity of Aflatoxin B1 and Ochratoxin A after simultaneous application of the in vivo micronucleus and comet assay

“…Besides, in some studies, an inhibition of the pathways regulated by Nrf2 have been described in kidney but not in liver (Marin-Kuan et al, 2006;Cavin et al, 2007). Thus, the protection of OTA against AFB1 genotoxicity would not be explained through this mechanism.…”

Toxicogenomics and cancer pathogenesis

“…The depletion of these genes is likely to impair the defense potential of the cells, resulting in chronic elevation of oxidative stress in the kidney and could contribute to OTA carcinogenicity [12]. OTA is nephrotoxic produced by fungi and is suspected of being the main etiological agent responsible for human Balkan endemic nephropathy (BEN) and associated urinary tract tumours.…”