Discovery of systematic responses and potential biomarkers induced by ochratoxin A using metabolomics

Abstract

Ochratoxin A (OTA) is known to be nephrotoxic and hepatotoxic in rodents when exposed orally. To understand the systematic responses to OTA exposure, GC-MS- and ¹H-NMR-based metabolomic techniques together with histopathological assessments were applied to analyse the urine and plasma of OTA-exposed rats. It was found that OTA exposure caused significant elevation of amino acids (alanine, glycine, leucine etc.), pentose (ribose, glucitol, xylitol etc.) and nucleic acid metabolites (pseudouridine, adenosine, uridine). Moreover, myo-inositol, trimethylamine-oxide (TMAO), pseudouridine and leucine were identified as potential biomarkers for OTA toxicity. The primary pathways included the pentose phosphate pathway (PPP), the Krebs cycle (TCA), the creatine pathway and gluconeogenesis. The activated PPP was attributed to the high requirements for nicotinamide adenine dinucleotide phosphate (NADPH), which is involved in OTA metabolism through cytochrome P450. The elevated gluconeogenesis and TCA suggest that energy metabolism was involved. The up-regulated synthesis of creatinine reveals the elevated catabolism of proteins. These findings provide an overview of systematic responses to OTA exposure and metabolomic insight into the toxicological mechanism of OTA.

Graphical Abstract

Keywords:

• ochratoxin A
• systematic responses
• biomarker
• metabolic network
• rats

Acknowledgements

The Fundamental Research Funds for the Central Universities did not participate in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare no conflict of interest. All animal handling and procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals once the study received approval by the Institutional Animal Care and Use Committee at China Agricultural University, Food Science and Nutritional Engineering College, Beijing, China. All surgery was performed aseptically and every attempt was made to minimise pain and discomfort.