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A 3D Renal Microsphere Model Reveals Antagonism in Ochratoxin a and Citrinin Co-Exposure
Dongmei Wu1,2,3, Xiao Ning4, Yongli Ye1,2,3
1School of Food Science and Technology, International Joint Laboratory on Food Safety, Synergetic Innovation Center of Food Safety and Quality Control, Jiangnan University, Wuxi 214122, Jiangsu, P. R. China.
Abstract:
Ochratoxin A (OTA) and citrinin (CIT) are mycotoxins that frequently co-contaminate food, posing a significant risk of co-exposure. This study aimed to explore the renal injury effects of the co-exposure of these two mycotoxins, including the types of co-effects of OTA and CIT and their impact on endoplasmic reticulum stress (ERS) by utilizing a constructed 3D renal microsphere model (HK-2: EA.hy926: HEK293T = 4:1:1). In the renal microsphere model, co-exposure to OTA and CIT exhibited an antagonistic interaction at all tested concentrations (CI = 1.12-1.24). Mechanistically, co-exposure induced mitochondrial dysfunction and reactive oxygen species imbalance and activated the ERS pathway. ERS further amplified the inflammatory response, leading to increased secretion of pro-inflammatory cytokines. Transcriptome analysis indicates that the Hippo signaling pathway also contributes to the promotion of cellular damage. Our findings reveal a complex toxicological interaction between OTA and CIT and highlight the critical role of physiologically relevant models in ensuring accurate risk assessment.
Insights
Ochratoxin A and citrinin co-exposure in food shows an antagonistic effect on kidney cells, despite causing mitochondrial dysfunction and endoplasmic reticulum stress. This research uses a 3D renal model for accurate mycotoxin risk assessment.
Area of Science:
- Toxicology
- Cell Biology
- Biochemistry
Background:
- Ochratoxin A (OTA) and citrinin (CIT) are common food mycotoxins.
- Co-exposure presents a significant health risk due to potential synergistic toxic effects.
Purpose of the Study:
- To investigate the renal injury effects of combined OTA and CIT exposure.
- To elucidate the mechanisms of co-toxicity, including endoplasmic reticulum stress (ERS).
- To evaluate the utility of a 3D renal microsphere model for mycotoxin risk assessment.
Main Methods:
- A 3D renal microsphere model (HK-2: EA.hy926: HEK293T = 4:1:1) was constructed.
- Co-exposure effects of OTA and CIT on renal cells were analyzed.
- Mechanisms including mitochondrial function, reactive oxygen species (ROS), ERS, and inflammatory responses were assessed.
- Transcriptome analysis was performed to identify contributing pathways.
Main Results:
- OTA and CIT exhibited antagonistic interactions in the 3D renal model across tested concentrations.
- Co-exposure induced mitochondrial dysfunction, ROS imbalance, and activated the ERS pathway.
- ERS exacerbated inflammation via increased pro-inflammatory cytokine secretion.
- The Hippo signaling pathway was implicated in promoting cellular damage.
Conclusions:
- The study reveals a complex, antagonistic toxicological interaction between OTA and CIT in the kidney.
- Endoplasmic reticulum stress and inflammation are key pathways in OTA and CIT co-toxicity.
- Physiologically relevant 3D models are crucial for accurate mycotoxin risk assessment.
