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Evaluation of toxicological mechanisms of ochratoxin-A in human primary proximal tubule epithelial cells

ABSTRACT: Ochratoxin-A (OTA) is a fungal mycotoxin that is one of the most common food contaminants, ubiquitously found in a variety of foodstuffs worldwide. As a known nephrotoxin, hepatotoxin, and class II-b carcinogen, exposure to this compound is a major health concern. Specifically, OTA has been implicated as a potential agent in chronic kidney disease of unknown etiology (CKDu), an endemic form of chronic kidney disease that disproportionally affects rural agricultural communities and is thought to arise from environmental factors rather than diabetes and hypertension. A key pathological difference between CKDu and CKD is the degeneration of the kidney proximal tubule, where OTA has been shown to accumulate. The mechanism of OTA toxicity in the human kidney remains elusive, and this study aims to elucidate OTA-induced molecular toxicological pathways using primary human proximal tubule epithelial cells (PTECs). We demonstrated that the previously reported downregulation of NRF2 target antioxidant response elements is not due to a direct interaction between NRF2 and its cytosolic binder, KEAP1, evidenced by the lack of recovery of mRNA transcripts with co-administration of NRF2 agonists, sulforaphane or tert-butylhydroquinone. Furthermore, exposure to OTA (10 uM) induces 7192 differentially expressed genes, including key regulators of mitochondrial fission and fusion. This was confirmed at the cellular level by confocal microscopy, where a breakdown of the mitochondrial network was observed at 100 nM OTA. Furthermore, OTA was found to significantly induce reactive oxygen species (mROS) and inhibit basal mitochondrial oxidative phosphorylation as well as glycolysis through measurements of oxygen consumption rate and extracellular acidification, corroborating transcriptional findings that OTA induces hypoxic response elements. In conclusion, in this work we demonstrate that OTA causes mitochondrial dysfunction and reduced ATP production, leading to a senescent-like state in PTECs characteristic of renal disease progression. These findings provide insight into early toxicological endpoints induced by OTA which have been established as pathophysiological changes involved in chronic kidney disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289962 | GEO | 2025/12/10

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.

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Evaluation of toxicological mechanisms of ochratoxin-A in human primary proximal tubule epithelial cells

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