Determination of the epigenetic effects of ochratoxin in a human kidney and a rat liver epithelial cell line.
Epidemiological studies have implicated ochratoxin A (OTA), a fungal metabolic-contaminant of animal and human food sources, in Balkan Endemic Nephropathy and renal tumors. Many environmental toxicants operate through nongenotoxic mechanisms that epigenetically control gene expression leading to a diseased state. Gap junctional intercellular communication (GJIC) plays a central role in the epigenetic control of genes in which alteration of normal GJIC has been implicated in many human pathologies, including cancer, teratogenesis, reproductive dysfunction and peripheral neuropathies. The cell proliferative stages of human diseases, such as cancer, also involves the induction of signal transduction pathways controlling the mitogenic steps, in which the mitogen activated protein kinases (MAPK), such as extracellular receptor kinase (ERK) and p38, are central to mitogenesis. We therefore determined the effects of OTA on GJIC and MAPK in a human kidney and rat liver epithelial cell line. OTA reversibly inhibited GJIC at noncytotoxic doses in the rat liver but not the human kidney cell line. Similarly, OTA was also a strong activator of MAPK, ERK and p38, in the rat liver cells but only weakly activated ERK and had no affect on p38 in the human kidney cell line. Another hallmark of human diseases is an abnormal alteration of apoptosis, also known as programmed cell death. We used our myc-transfected cell line, which exhibits higher levels of apoptosis, to test the effects of OTA on apoptosis. OTA greatly induced apoptosis in this cell line, which is contrary to the effects of most tumor promoters. In summary, OTA exhibits tumor promoting properties in the liver, but the effects of OTA on the human kidney epithelial cells suggested a lack of tumorigenic activity assuming that these epithelial cells, like the rat liver epithelial cells, are a primary target for carcinogens. These results also indicate that the nephrotoxicity of OTA either does not involve GJIC, assuming these epithelial cells play a vital role in kidney physiology, or that a more differentiated kidney cell type is the target for OTA toxicity, of which the role of GJIC remains unknown.
Horvath
Anelia
A
Department of Chemistry and Biochemistry, Medical University of Sofia, Sofia, Bulgaria.
Upham
Brad L
BL
Ganev
Varban
V
Trosko
James E
JE
D000818:Animals; D017209:Apoptosis; D002273:Carcinogens / Q000009:adverse effects* / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects* / Q000378:metabolism; D009793:Ochratoxins / Q000009:adverse effects* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D009793:Ochratoxins; C025589:ochratoxin A; D020929:Mitogen-Activated Protein Kinase Kinases