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Toxins 2011, 3(6), 504-519; doi:10.3390/toxins3060504

1H NMR Spectroscopy-Based Metabolomic Assessment of Uremic Toxicity, with Toxicological Outcomes, in Male Rats Following an Acute, Mid-Life Insult from Ochratoxin A

1
Centre for Environmental Policy, Imperial College London, London, SW7 2AZ, UK
2
Investigative Preclinical Toxicology, GlaxoSmithKline R&D, Park Road, Ware, Herts, SG12 0DP, UK
3
Waters Corporation, Milford, MA 01757, USA
*
Author to whom correspondence should be addressed.
Received: 13 March 2011 / Revised: 19 May 2011 / Accepted: 23 May 2011 / Published: 26 May 2011
(This article belongs to the Special Issue Uremic Toxins)
View Full-Text   |   Download PDF [223 KB, 30 May 2011; original version 26 May 2011]   |  

Abstract

Overt response to a single 6.25 mg dose of ochratoxin A (OTA) by oral gavage to 15 months male rats was progressive loss of weight during the following four days. Lost weight was restored within one month and animals had a normal life-span without OTA-related terminal disease. Decline in plasma OTA concentration only commenced four days after dosing, while urinary excretion of OTA and ochratoxin alpha was ongoing. During a temporary period of acute polyuria, a linear relationship between urine output and creatinine concentration persisted. Elimination of other common urinary solutes relative to creatinine was generally maintained during the polyuria phase, except that phosphate excretion increased temporarily. 1H NMR metabolomic analysis of urine revealed a progressive cyclic shift in the group principal components data cluster from before dosing, throughout the acute insult phase, and returning almost completely to normality when tested six months later. Renal insult by OTA was detected by 1H NMR within a day of dosing, as the most sensitive early indicator. Notable biomarkers were trimethylamine N-oxide and an aromatic urinary profile dominated by phenylacetylglycine. Tolerance of such a large acute insult by OTA, assessed by rat natural lifetime outcomes, adds a new dimension to toxicology of this xenobiotic.
Keywords: metabolomics; polyuria; ochratoxin A; pharmacokinetics; toxicology; nephropathy metabolomics; polyuria; ochratoxin A; pharmacokinetics; toxicology; nephropathy
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Mantle, P.G.; Nicholls, A.W.; Shockcor, J.P. 1H NMR Spectroscopy-Based Metabolomic Assessment of Uremic Toxicity, with Toxicological Outcomes, in Male Rats Following an Acute, Mid-Life Insult from Ochratoxin A. Toxins 2011, 3, 504-519.

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