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.

Ochratoxin A induces ER stress and apoptosis in mesangial cells via a NADPH oxidase-derived reactive oxygen species-mediated calpain activation pathway

“…It has been shown that OTA at a concentration of 1 μM significantly decreases the protein content in human mesangial cells; the cellular mechanism remains unknown [24]. OTA metabolism through cytochrome P450 requires high level of nicotinamide adenine dinucleotide phosphate (NADPH) which leads to activated pentose phosphate pathway (PPP) [25]. Excess of glucose entry is diverted through the PPP which possibly provided additional substrate for the enzyme NADPH oxidase [26].…”

Fisher Discrimination of Metabolic Changes in Rats Treated with Aspirin and Ibuprofen

“…Metabonomics is a useful tool for toxicity analysis, as it provides a unique mechanistic perspective on responses to toxicity [16,20,21,22]. In this study, we developed a GC-MS method to investigate blood metabolic changes in comparison to the blood biochemical indices ALT, AST, and AKP.…”

Serum Metabolomics in Rats after Acute Paraquat Poisoning

“…In order to explore the metabolic profile changes of acute paraquat poisoning in rats during different time periods, we compared the GC-MS spectrum of PLS-DA of the acute paraquat poisoning group (2,3,4,5,6,7,8,15, and 21 d after i.g. 36 mg/kg paraquat) with the rats in the control group (Fig.…”

“…4) In recent years, metabolomics has been widely applied to uncover biomarkers 5) and metabolic fingerprint in drug discovery and clinical toxicology, 6) especially to investigating systematic metabolic responses to toxins 7) and the associated mechanisms.…”

“…8) The primary goal of this study is to study systematically the metabolic pathway changes induced by paraquat in male rats after 2,3,4,5,6,7,8,15, and 21 d.…”