Chronic Exposure to Ochratoxin A Induces Metabolic Dysfunction‐Associated Steatotic Liver Disease‐Like Symptoms and Obesity With Sex‐Specific Effects in Zebrafish

Abstract

Ochratoxin A (OTA) is widely detected in foodstuffs including rice, wheat, and corn, making it urgent to assess its health risks to animals and humans. However, little is known about its impacts on metabolic dysfunction‐associated steatotic liver disease (MASLD) and obesity, particularly the underlying mechanism and sex differences. Here, we used zebrafish as the model organism and observed elevated fat accumulation in both sexes after exposure to 0, 0.01, and 0.1 µg/L of OTA for 3 months. However, only female fish exhibited the obesogenic effects. Both female and male livers exhibited vacuolar degeneration, inflammation, and lipid deposition upon OTA exposure, showing the features of MASLD. Quantitative lipidomic analysis further verified lipid metabolism disorder induced by OTA, characterized by increases in glycerolipids, glycerophospholipids, and several lipid subclass levels including triglycerides and lysophosphatidic acid. Transcriptomic and biochemical analysis demonstrated that disruption in adipocytokine signaling pathway and vitamin D deficiency explained the lipid remodeling in the female liver. Regarding males, activation of PPAR signaling pathway and ferroptosis contributed to the lipid remodeling. The present study revealed that MASLD‐like symptoms and obesity induced by OTA in animals exhibited sex differences. Overall, our results provide valuable insights for the health risk assessment of OTA and emphasize the need for tight regulation of OTA.