A 3D Renal Microsphere Model Reveals Antagonism in Ochratoxin a and Citrinin Co-Exposure

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.