Abstract
Ochratoxin A (OTA) is a widespread food toxin produced by Aspergillus ochraceus and other molds. In this study, we developed and established acute OTA toxicity conditions in mice, which received daily oral doses of OTA between 0.5 up to 8 mg/kg body weight up to 7 days and were subjected to histological and biochemical analysis to characterize renal and hepatic damage. Oral administration of OTA for 7 days resulted in loss of body weight in a dose-dependent manner and increased the levels of serum biomarkers of hepatic and renal damage. The kidney was more sensitive to OTA-induced damage than the liver. In addition to necrosis, OTA induced hepatic and renal apoptosis in dose- and time-dependent manners. Especially, a high dose of OTA (8 mg/kg body weight) administered for 7 days led to necroptosis in both liver and kidney tissues. OTA dose-dependently increased the oxidative stress levels, including lipid peroxidation, in the liver and kidneys. OTA disrupted mitochondrial dynamics and structure in hepatic and renal cells, leading to the dysregulation of mitochondrial homeostasis. OTA increased transferrin receptor 1 and decreased glutathione peroxidase 4 levels in a dose- and time-dependent manner. These results suggest the induction of ferroptosis. Collectively, this study highlighted the characteristics of acute OTA-induced hepatic and renal toxicity in mice in terms of oxidative stress, mitochondrial damage, and multiple cell death mechanisms, including necroptosis and ferroptosis.
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All data are included in the Results and Supplementary Information.
Abbreviations
- ALT:
-
Alanine aminotransferase
- AST:
-
Aspartate aminotransferase
- BCA:
-
Bicinchoninic acid
- BUN:
-
Blood urea nitrogen
- DAPI:
-
4′,6-Diamidino-2-phenylindole dihydrochloride
- DRP1:
-
Dynamin-related protein 1
- GAPDH:
-
Glyceraldehyde 3-phosphate dehydrogenase
- GPX4:
-
Glutathione peroxidase 4
- GSH:
-
Glutathione
- GSSG:
-
Oxidized GSH
- GSH/GSSG:
-
Ratio of reduced to oxidized GSH
- H&E:
-
Hematoxylin and eosin
- HNE:
-
4-Hydroxynonenal
- LDH:
-
Lactate dehydrogenase
- MFF:
-
Mitochondrial fission factor
- MLKL:
-
Mixed lineage kinase domain-like
- OTA:
-
Ochratoxin A
- PBS:
-
Phosphate-buffered saline
- OPA1:
-
Optic atrophy 1
- RIPK3:
-
Receptor-interacting protein kinase 3
- TfR1:
-
Transferrin receptor 1
- TEM:
-
Transmission electron microscopy
- TUNEL:
-
Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling
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Funding
This study was supported by grants from the National Research Foundation of Korea (grant numbers: 2019R1F1A1057412, 2022R1A2C2004099, and 2022R1A5A2018865) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI22C0530).
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Y.S. and H.-Y.K. designed research; Y.S. performed the experiments and prepared the figures; Y.S., H.J.L., D.R., J.-R.K., and H.-Y.K. analyzed the data; Y.S. and H.-Y.K. wrote the paper. All authors discussed and approved the final manuscript.
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Son, Y., Lee, H.J., Ryu, D. et al. Ochratoxin A induces hepatic and renal toxicity in mice through increased oxidative stress, mitochondrial damage, and multiple cell death mechanisms. Arch Toxicol 98, 2281–2295 (2024). https://doi.org/10.1007/s00204-024-03732-3
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DOI: https://doi.org/10.1007/s00204-024-03732-3