title: Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model.
abstract: Ochratoxin A (OTA) is a widely studied compound due to its role in renal toxicity and carcinogenicity. However, there is still no consensus on the exact mechanisms of toxicity or carcinogenicity. In the current study, we analysed the effect of OTA on three human renal proximal tubular models (human primary, RPTEC/TERT1 and HK-2 cells) and two rat renal proximal tubular models (rat primary and NRK-52E cells). Global transcriptomics analysis at two exposure times was performed to generate a set of 756 OTA sensitive genes. This gene set was then compared in more detail across all models and additionally to a rat in vivo renal cortex model. The results demonstrate a well-conserved response across all models. OTA resulted in deregulation of a number of pathways including cytoskeleton, nucleosome regulation, translation, transcription, ubiquitination and cell cycle pathways. Interestingly, the oxidative stress activated Nrf2 pathway was not enriched. These results point to an epigenetic action of OTA, perhaps initiated by actin binding as the actin remodelling gene, advillin was the highest up-regulated in all models. The largest model differences were observed between the human and the rat in vitro models. However, since the human in vitro models were more similar to the rat in vivo model, it is more likely that these differences are model-specific rather than species-specific per se. This study demonstrates the usefulness of in vitro cell culture models combined with transcriptomic analysis for the investigation of mechanisms of toxicity and carcinogenicity. In addition, these results provide further evidence supporting a non-genotoxic mechanism of OTA-induced carcinogenicity.
authors: Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Fritz-Pregl Strasse 3, 6020 Innsbruck, Austria. paul.jennings@i-med.ac.at
authors: Paul
authors: P
authors: Jennings
authors: Christina
authors: C
authors: Weiland
authors: Alice
authors: A
authors: Limonciel
authors: Katarzyna M
authors: KM
authors: Bloch
authors: Robert
authors: R
authors: Radford
authors: Lydia
authors: L
authors: Aschauer
authors: Tara
authors: T
authors: McMorrow
authors: Anja
authors: A
authors: Wilmes
authors: Walter
authors: W
authors: Pfaller
authors: Hans J
authors: HJ
authors: Ahr
authors: Craig
authors: C
authors: Slattery
authors: Edward A
authors: EA
authors: Lock
authors: Michael P
authors: MP
authors: Ryan
authors: Heidrun
authors: H
authors: Ellinger-Ziegelbauer
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D004247:DNA / Q000187:drug effects* / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D008297:Male; D009183:Mycotoxins / Q000633:toxicity*; D009793:Ochratoxins / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D018675:Toxicity Tests
chemical_list: D002273:Carcinogens; D009183:Mycotoxins; D009793:Ochratoxins; C025589:ochratoxin A; D004247:DNA