Whole transcriptome analysis of human kidney cells after exposure to Ochratoxin A
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE133831 | GEO | 2020/01/15
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.
2020-10-22 | GSE151776 | GEO
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.
2016-10-28 | GSE89256 | GEO
Project description:Ochratoxin A (OTA) is a fungal secondary metabolite widely found in cereal and a wide variety of foods; it also exhibits carcinogenic effects, nephrotoxicity, and teratogenicity. In this study, the zebrafish was applied to investigate the effects of ochratoxin A on gene expressions in zebrafish embryos.
2018-07-16 | GSE71345 | GEO
Project description:Ochratoxin A gene expression profiling in liver and kidney, with time points of exposure from 7 days to 12 motnhs Keywords: timecourse
2005-12-19 | GSE2852 | GEO
Project description:The objective of this study is to analyze miRNA profiling in the kidneys of rats gavaged with OTA. To profile miRNAs in the kidneys of rats with OTA nephrotoxicity, high-throughput sequencing and bioinformatics approaches were applied to analyze the miRNAs in the kidney of rats following OTA treatment
2014-06-01 | E-MTAB-2475 | biostudies-arrayexpress
Project description:Ochratoxin A gene expression profiling in liver and kidney, with time points of exposure from 7 days to 12 months Experiment Overall Design: three replicates for each timepoint measured, control and ochratoxin A treated for both liver and kidney. <br><br>Note that files GSM62732.CEL and GSM62733.CEL, and files GSM62730.CEL and GSM62739.CEL as downloaded from GEO contain identical data.
2007-10-10 | E-GEOD-2852 | biostudies-arrayexpress
Project description:The aim of this study was to reveal the genomic response of yeast cells to the related mycotoxins citrinin (CIT) and ochratoxin A (OTA). Both mycotoxins can be produced by the same filamentous fungi and co-contaminate the same foodstuff. However, it is not known whether CIT and OTA share the same toxicity mechanisms or not. We performed transcriptomic profiling experiments using microarray hybridization of a pdr5 mutant strain exposed separately to CIT or OTA and exposed to a combination of both toxins. A yeast pdr5 mutant was used, because it is significantly sensitized to both toxins. We find that CIT and OTA cause the rapid activation of largely non-overlapping gene sets. The most prominent functional group of CIT-activated genes corresponds to the cellular response to oxidative stress, while OTA-activated genes belong predominantly to single organism developmental processes and meiosis/sporulation. The combined exposure of CIT and OTA revealed a mixed response of functional gene groups. Our results demonstrate that CIT and OTA have distinguishable and independent biological effects with oxidative stress being a hallmark for CIT toxicity and the deregulation of developmental genes being the principal feature for OTA toxicity.
2016-10-01 | GSE84187 | GEO
Project description:We report the transcriptome and miRNAome of human embryonic kidney 293 cells upon the administration of ochratoxin A (OTA) and citrinin (CTN), to compare the individual and combined toxicity of these two mycotoxins. We identified largely differentially expressed miRNAs and corresponding genes, and the correlations between miRNAs and their target genes associated with apoptotic signaling were furthermore analyzed by pmi-RB-REPORT luciferase assay system. We concluded that hsa-miR-1-3p plays an essential role in promoting OTA and CTN-induced renal cytotoxicity.
2017-12-31 | GSE93148 | GEO
Project description:The multiple toxic effects of Ochratoxin A(OTA) are a real threat for human beings and animal health. It has been suggested that probiotic improve the epithelial barrier disruption and reduce cell damage induced by mycotoxins. However, the exact effect and mechanism of probiotic Bacillus subtilis CW14 on epithelial barrier function is not well understood. The aim of this study was to examine whether B. subtilis CW14 could protect against OTA-induced barrier disruption and cell damage in human intestinal epithelial cell line (Caco-2). The results showed that OTA was absorbed efficiently in Caco-2 cells, led to microvilli disruption and tight junction protein(ZO-1 and claudin-1) damage, and suppressed cell proliferation by arresting cell cycle in G2/M phase and promoting apoptosis. The addictive of B. subtilis CW14 strains could partially reversed the tight junction injury by improving the ZO-1 protein expression and reduced the apoptosis induced by OTA. Furthermore, the transcriptome analysis data indicated that OTA mainly down-regulated the gene expression involved in tight junctions, cell cycle, and apoptosis-related signaling pathways. While the B. subtilis CW14 has the potential to protect epithelial barrier through activating the toll-like receptor signaling pathway, and could partially repair the OTA damage by down-regulating the TRAIL death receptor genes and up-regulating the DNA repair genes. Our findings suggest an important implication for the role of B. subtilis CW14 on the regulation of tight junction proteins and reduction cell death in intestine epithelial cells, and that is a potential candidate as a food additive to protect against intestinal damage.
2019-12-31 | GSE115081 | GEO
Project description:Aflatoxin M1 (AFM1) is a common mycotoxin in dairy milk and it is typically concurrently present with other mycotoxins that may represent a threat for food safety. However, knowledge on how AFM1, alone or in combination with other mycotoxins may affect human intestinal epithelial integrity remain to be established. We employed transcriptome and proteome analysis integrated with biological validation to reveal the molecular basis underlining the effect AFM1 and/or ochratoxin A (OTA) exposure on intestinal epithelial integrity of differentiated Caco-2 cells. Exposure to 4 μg/ml of OTA was found to disrupt human gut epithelial integrity, whereas 4 μg/ml of AFM1 did not. Integrated transcriptome and proteome analysis of AFM1 and OTA, alone or in combination, indicate synergistic effect of the two mycotoxins in disrupting intestinal integrity. This effect was mechanistically linked to a broad ranges of pathways related to intestinal integrity enriched by down-regulated genes and proteins, associated to focal adhesion, adherens junction, and gap junction pathways. Furthermore, the cross–omics analysis of mixed AFM1 and OTA compared with OTA alone suggest that kinases family members, including MLCK, MAPKs, and PKC are the potential key regulators on modulating intestinal epithelial integrity. These findings provide novel insight into the synergistic detrimental role of multiple mycotoxins in disrupting intestinal integrity, and, therefore, identify potential target to improve milk safety related to human health.
2018-08-08 | PXD009437 | Pride