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Renal gene expression changes in p53 heterozygous and p53 homozygous mice due to chronic dietary exposure to the mycotoxin ochratoxin A

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE89256 | GEO | 2016/10/28

SECONDARY ACCESSION(S): PRJNA350844

REPOSITORIES: GEO

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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.

Project description:Previously we demonstrated that the mouse liver tumor response to the non-genotoxic carcinogens oxazepam [CAS:604-75-1;CHEBI:7823] and Wyeth-14,643 [CAS:50892-23-4;CHEBI:32509] involved more differences than similarities in changes in early gene expression. In this study we used quantitative real-time PCR and oligonucleotide microarray analysis to identify genes that were up- or downregulated in mouse liver early after treatment with different known carcinogens, including oxazepam [CAS:604-75-1 CHEBI:7823] (125 and 2500 p.p.m.), o-nitrotoluene [CAS:88-72-2;CHEBI:33098] (1250 and 5000 p.p.m.) and methyleugenol [CAS:93-15-2;CHEBI:4918] (75 mg/kg/day), or the non-carcinogens p-nitrotoluene [CAS:99-99-0;CHEBI:33097] (5000 p.p.m.), eugenol [CAS:97-53-0;CHEBI:4917] (75 mg/kg/day) and acetaminophen [CAS:103-90-2;CHEBI:2386] (6000 p.p.m.). Starting at 6 weeks of age, mice were treated with the different compounds for 2 weeks in the diet, at which time the livers were collected. First, expression of 12 genes found previously to be altered in liver after 2 weeks treatment with oxazepam and/or Wyeth-14,643 was examined in livers from the various chemical treatment groups. These gene expression changes were confirmed for the livers from the oxazepam-treated mice in the present study, but were not good early markers for all the carcinogens in this study. In addition, expression of 20 842 genes was assessed by oligonucleotide microarray [n ¼ 4 livers/group, 2 hybridizations/liver (with fluor reversals)] and the results were analyzed using the Rosetta Resolver System and GeneSpring software. The analyses revealed that several cancer-related genes, including Fhit, Wwox, Tsc-22 and Gadd45b, were induced or repressed in unique patterns for specific carcinogens and not altered by the non-carcinogens. The data indicate that even if the tumor response, including molecular alterations, is similar, such as for oxazepam and methyleugenol, early gene expression changes appear to be carcinogen specific and seem to involve apoptosis and cell cyclerelated genes.

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Renal gene expression changes in p53 heterozygous and p53 homozygous mice due to chronic dietary exposure to the mycotoxin ochratoxin A

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