title: 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 (1)H-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.
authors.affiliation: a Laboratory of Food Safety and Molecular Biology, College of Food Science and Nutritional Engineering , China Agricultural University , Beijing , China.
authors.forename: Kai
authors.initials: K
authors.lastname: Xia
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: He
authors.forename: Qiu
authors.initials: Q
authors.lastname: Dai
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Cheng
authors.forename: Xiaozhe
authors.initials: X
authors.lastname: Qi
authors.forename: Mingzhang
authors.initials: M
authors.lastname: Guo
authors.forename: YunBo
authors.initials: Y
authors.lastname: Luo
authors.forename: Kunlun
authors.initials: K
authors.lastname: Huang
authors.forename: Changhui
authors.initials: C
authors.lastname: Zhao
authors.forename: Wentao
authors.initials: W
authors.lastname: Xu
mesh_terms: D000818:Animals; D015415:Biomarkers; D002273:Carcinogens / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055442:Metabolome; D055432:Metabolomics; D009793:Ochratoxins / Q000633:toxicity*; D051381:Rats
chemical_list: D015415:Biomarkers; D002273:Carcinogens; D009793:Ochratoxins; C025589:ochratoxin A; D003577:Cytochrome P-450 Enzyme System
keywords: biomarker; metabolic network; ochratoxin A; rats; systematic responses