Expression data from Aristolochic Acid and Ochratoxin A treated Tsc2 mutant (Eker) and corresponding wild type rats
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE5923 | GEO | 2007/08/23
SECONDARY ACCESSION(S): PRJNA97369
REPOSITORIES: GEO
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Project description:Renal gene expression profiles of Eker and wild type rats, gavaged with AA or OTA, respectively for 1, 3, 7 or 14 days; We used Affymetrix RAE230A microarrays for the analysis of early gene expression changes in the renal cortex_ outer medulla of carcinogen treated Eker and corresponding wild type rats Experiment Overall Design: Eker and wild type rats were gavaged daily with OTA (210µg_ kg BW) or AA (10mg_ kg BW), dissolved in 0,1M sodium bicarbonate. Time-matched vehicle controls were gavaged with 0,1M sodium bicarbonate. Following 1, 3, 7, and 14 days of treatment, Narcoren (pentobarbital) anesthetized rats were sacrificed by exsanguination subsequent to retrograde perfusion with PBS. Left kidneys were collected, cross-sectioned into 5mm slices and stored in RNAlater for subsequent RNA isolantion and chip hybridisation
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Project description:Ochratoxin A (OTA) is one of the most abundant mycotoxin contaminants in food stuffs and possesses carcinogenic, nephrotoxic, teratogenic and immunotoxic properties. Especially, severe nephrotoxicity is of great concern, as characterized by degeneration of epithelial cells of the proximal tubules and interstitial fibrosis. However, its mechanism of toxicity, hazard identification as well as genetic risk factors contributing to OTA toxicity in humans has been elusive due to the lack of adequate models that fully recapitulate kidney function in vitro. The present study attempts to evaluate dose-response relationships, identify the contribution of active transport proteins that govern renal disposition of OTA, and determine the role of metabolism in bioactivation and detoxification of OTA using a 3D human kidney proximal tubule microphysiological system (kidney MPS). We demonstrated that IC50 values of OTA in kidney MPS culture (0.375 – 1.21 µM) were in good agreement with clinical toxic concentrations of OTA in urine. Surprisingly, no enhancement of kidney injury biomarkers was evident in the effluents of kidney MPS after OTA exposure despite significant toxicity observed by LIVE/DEAD staining, rather these biomarkers were decreased in OTA concentration-dependent manner. Furthermore, the effect of 1-aminobenzotriazole (ABT) and 6-(NBD-4-ylthio-) hexanol (NBDHEX), pan-inhibitor of P450 and GST enzymes, respectively, on the OTA-induced toxicity in kidney MPS was examined, which resulted in significant enhancement of OTA-induced toxicity by NBDHEX (3 µM) treatment whereas ABT (1 mM) treatment decreased OTA-induced toxicity, suggesting the roles of GSTs and P450 enzymes in the detoxification and bioactivation of OTA, respectively. Additionally, OTA transport studies using kidney MPS in the presence and absence of inhibitor of organic anion transporter(s), probenecid (1 mM), revealed the role of organic anionic membrane transporter(s) in the kidney specific disposition of OTA. Our findings provide a better understanding of the mechanism of OTA-induced kidney injury which may support changes in risk assessment, regulatory agency policies on allowable exposure levels and determination of genetic factors in high-risk populations against OTA nephrotoxicity.
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Project description:Changes in renal gene expression were assessed in p53WT(+/+) mice and their heterozygous p53TG(+/-) counterparts exposed to the nephrotoxic and tumourigenic fungal toxin Ochratoxin A (OTA) in their diet for 26 weeks. The p53TG mouse model has been used in screening for potential carcinogens as it displays increased sensitivity to genotoxic carcinogens. Comparison between the effects of OTA in diet on male mice of these two strains was assessed at 0, 0.05, 2.0, 10.0 mg OTA/kg diet. Changes in global gene expression were compared using Agilent Mouse oligonucleotide microarray analysis of kidneys from control (0 mg OTA/kg diet) and treated (2 mg OTA/kg diet) mice. Significant changes in gene expression associated with cell cycle regulation, DNA damage repair, tumour suppression and apoptosis were consistent with nephrotoxicity due to OTA exposure in both mouse strains. Changes in genes related to oxidative stress and free radical scavenging may contribute to the down-regulation by OTA of genes associated with metabolism. Gene expression changes were consistent with phenotype and provided insight on the cellular responses to chronic OTA exposure.
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Project description:Microarrays were used to analyse gene expression underlying early tumourigenesis in Eker rats. Distinct classes of up- and downregulated genes were identified in different preneoplasic lesion vs. microdissected normal (healthy) renal tubules. Laser capture microdissected renal basophilic atypical tubule (bAT) and basophilic atypical hyperplasia (bAH) and healthy tissue (HT) of 6-months aristolochic acid (AA)- and ochratoxin A (OTA)-treated and control (C) male Eker rats were isolated for RNA extraction and microarray analysis in order to investigate gene expression profiles induced by AA and OTA as well as to differentiate pathways specific for the bAT to bAH progression. Keywords: gene expression study, preneoplasic lesion vs. microdissected normal renal tubules For microdissection of preneoplastic lesions from H&E stained renal cryosections, a PALM laser microdissection and pressure catapulting (LMPC) system (PALM Microlaser GmbH) was used. Atypical tubule (bAT), basophilic atypical hyperplasia (bAH) or healthy tissue (HT) were micodissected separately from each of three replicatemale Eker rats per dose group. Lesions of each type or HT from each individual animal were pooled. RNA isolation from pooled samples and subsequent Affymetrix Rat Genome RAE_230A_2.0 chip hybridization was carried out as previously described (Stemmer et al., Toxicology and Applied Pharmacology(2006) Nov 15;217(1):134-42). Time matched controls for microarrays from lesions of OTA and AA treated rats are specified as C(AA) and C(OTA).
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Project description:Microarrays were used to analyse gene expression underlying early tumourigenesis in Eker rats. Distinct classes of up- and downregulated genes were identified in different preneoplasic lesion vs. microdissected normal (healthy) renal tubules. Laser capture microdissected renal basophilic atypical tubule (bAT) and basophilic atypical hyperplasia (bAH) and healthy tissue (HT) of 6-months aristolochic acid (AA)- and ochratoxin A (OTA)-treated and control (C) male Eker rats were isolated for RNA extraction and microarray analysis in order to investigate gene expression profiles induced by AA and OTA as well as to differentiate pathways specific for the bAT to bAH progression. Keywords: gene expression study, preneoplasic lesion vs. microdissected normal renal tubules
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