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.