Dynamic changes of global DNA methylation and hypermethylation of cell adhesion-related genes in rat kidneys in response to ochratoxin A

Abstract

Ochratoxin A (OTA), which is found in a variety of food products, is associated with the development of nephrotoxicity and carcinogenicity in rats and has raised public health concerns. A previous study in our laboratory indicated that OTA exposure induced cytotoxicity by decreasing global DNA methylation in vitro. However, the relationship between OTA-induced nephrotoxicity and DNA methylation changes in vivo remains unclear. The object of this study was to investigate whether OTA can change global DNA methylation or alter the expression of several critical tumour-related genes by inducing methylation modifications before carcinogenesis. We focused on the mechanism of action of OTA in regard to DNA methylation, including the expression of DNA methyltransferases and the regulation of specific cell signalling pathways. Dynamic and dose-dependent changes of global DNA methylation were observed during OTA-induced nephrotoxicity and probably associated with the expression of DNA methyltransferase 1. 13-week exposure of OTA caused hypermethylation in the promoters of critical cell adhesion-related genes, E-cadherin and N-cadherin, leading to reduction of the corresponding mRNA expression, accompanied by transcriptional activation of the Wnt and PI3K/AKT pathways. These findings suggested that long-term OTA exposure could disrupt DNA methylation profile, which might be one of the possible mechanisms of OTA-induced nephrotoxicity.

Mycotoxins and oxidative stress: where are we?

“…As human and animal exposure to mycotoxins is unavoidable, effective ways to mitigate their harmful impacts are required. Several studies have demonstrated the beneficial effects of antioxidant substances in the prevention and treatment of various diseases (Li et al, 2015). In this context, the use of natural antioxidants has been shown to mitigate and/or prevent the toxic effects of mycotoxins (Sorrenti et al, 2013).…”

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].…”

The Impact of Natural Dietary Compounds and Food-Borne Mycotoxins on DNA Methylation and Cancer

“…Some of the main food-borne mycotoxins—fusaric acid, fumonisin B 1 , deoxynivalenol, T-2 toxin, zearalenone, ochratoxin A, and aflatoxin B 1 ( Figure 4 )—have been shown to induce a change in the DNA methylation profile in human cell lines and animal models [ 213 , 214 , 215 , 216 , 217 , 218 , 219 ].…”

“…Another study by Li et al investigated the effects of low (70 µg/kg) and high (210 µg/kg diet) OTA intake on global DNA methylation in rat kidneys after 4, 13, and 26 weeks of consumption. After 4 weeks, global DNA methylation was reduced in rat kidneys exposed to a high dose of OTA, while low-dose OTA treatment showed no change in methylation [ 215 ]. Remarkably, after 13 weeks, the kidneys of both low and high-dose OTA-treated rats showed a significant increase in global DNA methylation [ 215 ].…”