Metabonomic Evaluation of Melamine-Induced Acute Renal Toxicity in Rats

Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina 28081, USA.
Journal of Proteome Research (Impact Factor: 5). 07/2009; 9(1):125-33. DOI: 10.1021/pr900333h
Source: PubMed

ABSTRACT The recent outbreak of renal failure in infants in China has been determined to be caused by melamine (Mel) and derivatives adulterated in the food. A metabonomic study was performed to evaluate the global biochemical alteration triggered by Mel ingestion in parallel with the acute renal toxicity in rats. Mel at 600, 300, and 100 mg/kg, cyanuric acid (Cya) at 100 mg/kg, and mixture of Mel and Cya (50 mg/kg each) were administered in five groups of Wistar rats, respectively, via oral gavage for 15 days. Urinary metabonomic profiles indicated that Mel perturbed urinary metabolism in a dose-dependent manner, with high-dose group showing the most significant impact. Metabonomic variations also suggest that the toxicity of low-dose (50 mg/kg) Mel was greatly elevated by the presence of Cya (at 50 mg/kg), which was able to induce a significant metabolic alteration to a level equivalent to that of 600 mg/kg Mel. Histological examination and serum biochemical analysis also indicated that the low-dose Mel-Cya mixture and high-dose Mel group resulted in the greatest renal toxicity. The high-dose Mel and low-dose Mel-Cya resulted in disrupted amino acid metabolism including tryptophan, polyamine, and tyrosine metabolism, and altered TCA and gut microflora structure.

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    • "rough the analysis of one or several kinds of bio�uids including serum, urine, saliva, and tissue samples, the global and dynamic alterations in metabolism can be deciphered [4]. erefore, metabolomics has been increasingly used in many applications such as identifying metabolite markers for clinical diagnosis and prognosis [5], monitoring the chemical-induced toxicity [6], exploring the potential mechanism of diverse diseases [7], and assessing therapeutic effects of treatment modalities [8] [9]. Univariate and/or multivariate statistical methods are routinely used in metabolomics studies, aiming at successful classi�cation of samples with metabolic phenotypic variations and identi�cation of potential biomarkers while minimizing the technical variations. "
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    ABSTRACT: Metabolomic data analysis becomes increasingly challenging when dealing with clinical samples with diverse demographic and genetic backgrounds and various pathological conditions or treatments. Although many classification tools, such as projection to latent structures (PLS), support vector machine (SVM), linear discriminant analysis (LDA), and random forest (RF), have been successfully used in metabolomics, their performance including strengths and limitations in clinical data analysis has not been clear to researchers due to the lack of systematic evaluation of these tools. In this paper we comparatively evaluated the four classifiers, PLS, SVM, LDA, and RF, in the analysis of clinical metabolomic data derived from gas chromatography mass spectrometry platform of healthy subjects and patients diagnosed with colorectal cancer, where cross-validation, R (2)/Q (2) plot, receiver operating characteristic curve, variable reduction, and Pearson correlation were performed. RF outperforms the other three classifiers in the given clinical data sets, highlighting its comparative advantages as a suitable classification and biomarker selection tool for clinical metabolomic data analysis.
    Evidence-based Complementary and Alternative Medicine 02/2013; 2013:298183. DOI:10.1155/2013/298183 · 1.88 Impact Factor
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    • "Recent outbreak of renal failure in infants in China has been REVIEW determined to be caused by melamine and derivatives adulterated in the food. Metabonomics was performed to evaluate the global biochemical alteration triggered by melamine ingestion in parallel with the acute renal toxicity in rats (Xie et al. 2010). "
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    ABSTRACT: Metabonomics has played increasingly important roles in pharmaceutical research and development. Safety assessment of drugs is a key stage in drug development and one which represents a significant attritional hurdle. However, characterization of the molecular mechanisms of drug toxicity still remains an enormous challenge. Recent advancements in 'omics' sciences, and in particular metabonomics, has enabled some elucidation or insights into toxicological sequelae. Metabonomics is a global metabolic profiling framework which utilizes high resolution analytics together with chemometric statistical tools to derive an integrated picture of both endogenous and xenobiotic metabolism. Hepatotoxicity and nephrotoxicity are major reasons that drugs are withdrawn post-market, and hence it is of major concern to both the Food and Drug Administration and pharmaceutical companies. There is a strong need to develop reliable biomarkers that can accurately predict toxicity in the drug discovery and development process and are translatable to the clinic. A deeper understanding of global perturbations in biochemical pathways and useful biomarkers could provide valuable insights about mechanisms of toxicity. This review summarizes some current progress in the application of metabonomic in understanding drug-induced hepatotoxicity and nephrotoxicity, with an emphasis on identifying early toxicity biomarkers.
    Pharmazie 02/2012; 67(2):99-105. DOI:10.1691/ph.2012.1104 · 1.00 Impact Factor
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    • "Low dose of melamine, such as 24 mg kg body weight and 33 mg kg body weight, had no significant effect on the change of body weight, neither did the formation of renal calculi (Kobayashi et al., 2010; Stine et al., 2011). Compared to the low dose of 100 mg kg body weight, melamine at 300 mg kg body weight could induce toxicity, however, it did not cause seriously damage induced by the high dose group of 600 mg kg body weight (Xie et al., 2010). In addition, referred to the effective dosage of latest study, melamine ingested by pregnant female rats at a dose of 400 mg/day bodyweight not only affected the female rats themselves but also could significantly affect plasma creatinine , plasma uric acid and blood urea nitrogen concentrations in their infant rats (Jingbin et al., 2010). "
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    ABSTRACT: Many studies reported that infants and animals were affected by food containing melamine, and the renal pathology was the main manifestation in intoxicated case. Our previous studies showed that melamine could impair hippocampal function and inhibited differentiated PC12 cell proliferation in vitro. The present study aimed to examine the effect on hippocampus and the possible mechanism induced by melamine in vivo. To address the hypothesis that melamine would impair the hippocampal function in vivo and then induce cognitive deficits, male Wistar rats were used to establish an animal model and melamine administered at a dose of 300 mgkg/day for 4 weeks. Morris water maze (MWM) test was employed to evaluate the learning and memory. The long term potentiation (LTP) from Schaffer collaterals to CA1 region in the hippocampus was recorded. The result of MWM test showed that there were significant deficits of learning and memory induced by melamine. LTP test presented that field excitatory postsynaptic potentials (fEPSPs) slopes were significantly lower in melamine group compared to that in control group. In conclusion, melamine had a toxic influence on hippocampus, which induced the learning and memory deficits. It suggested that the potential mechanism was associated with impairments of synaptic plasticity.
    Toxicology Letters 08/2011; 206(3):276-80. DOI:10.1016/j.toxlet.2011.08.009 · 3.36 Impact Factor
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