TY - JOUR
T1 - Effects of feeding and body weight loss on the 1H-NMR-based urine metabolic profiles of male Wistar Han rats
T2 - Implications for biomarker discovery
AU - Connor, Susan C.
AU - Wu, Wen
AU - Sweatman, Brian C.
AU - Manini, Jodi
AU - Haselden, John N.
AU - Crowther, Daniel J.
AU - Waterfield, Catherine J.
PY - 2004
Y1 - 2004
N2 - For almost two decades, 1H-NMR spectroscopy has been used as an 'open' system to study the temporal changes in the biochemical composition of biofluids, including urine, in response to adverse toxic events. Many of these in vivo studies have reported changes in individual metabolites and patterns of metabolites that correlated with toxicological changes. However, many of the proposed novel biomarkers are common to a number of different types of toxicity. These may therefore reflect non-specific effects of toxicity, such as weight loss, rather than a specific pathology. A study was carried out to investigate the non-specific effects on urinary metabolite profiles by administering four hepatotoxic compounds, as a single dose, to rats at two dose levels: hydrazine hydrate (0.06 or 0.08 g kg-1), 1,2-dimethylhydrazine (0.1 or 0.3 g kg-1), α-napthylisothiocyanate (0.1 or 0.15 g kg-1) and carbon tetrachloride (1.58 or 3.16 g kg-1). The study included weight-matched control animals along with those that were dosed, which were then 'pair-fed' with the treated animals so they achieved a similar weight loss. The urinary metabolite profiles were investigated over time using 1H-NMR spectroscopy and compared with the pathology from the same animals. The temporal changes were analysed statistically using multivariate statistical data analysis including principal component analysis, partial least squares, parallel factor analysis and Fisher's criteria. A number of metabolites associated with energy metabolism or which are partially dietary in origin, such as creatine, creatinine, tricarboxylic acid (TCA) cycle intermediates, phenylacetylglycine, fumarate, glucose, taurine, fatty acids and N-methylnicotinamide, showed altered levels in the urine of treated and pair-fed animals. Many of these changes correlated well with weight loss. Interestingly, there was no increase in ketone bodies (acetate and β-hydroxybutyrate), which might be expected if energy metabolism was switched from glycolysis to fatty acid β-oxidation. In some instances, the metabolites that changed were consideredto be nonspecific markers of toxicity, but were also identified as markers of a specific type of toxicity. For example, taurine was raised significantly in carbon tetrachloride-treated animals but reduced in the pair-fed group. However, raised urinary bile acid levels were only seen after α -napthylisothiocyanate treatment. The methodology, statistical analysis used and the data generated will help improve the identification of specific markers or patterns of urinary markers of specific toxic effects.
AB - For almost two decades, 1H-NMR spectroscopy has been used as an 'open' system to study the temporal changes in the biochemical composition of biofluids, including urine, in response to adverse toxic events. Many of these in vivo studies have reported changes in individual metabolites and patterns of metabolites that correlated with toxicological changes. However, many of the proposed novel biomarkers are common to a number of different types of toxicity. These may therefore reflect non-specific effects of toxicity, such as weight loss, rather than a specific pathology. A study was carried out to investigate the non-specific effects on urinary metabolite profiles by administering four hepatotoxic compounds, as a single dose, to rats at two dose levels: hydrazine hydrate (0.06 or 0.08 g kg-1), 1,2-dimethylhydrazine (0.1 or 0.3 g kg-1), α-napthylisothiocyanate (0.1 or 0.15 g kg-1) and carbon tetrachloride (1.58 or 3.16 g kg-1). The study included weight-matched control animals along with those that were dosed, which were then 'pair-fed' with the treated animals so they achieved a similar weight loss. The urinary metabolite profiles were investigated over time using 1H-NMR spectroscopy and compared with the pathology from the same animals. The temporal changes were analysed statistically using multivariate statistical data analysis including principal component analysis, partial least squares, parallel factor analysis and Fisher's criteria. A number of metabolites associated with energy metabolism or which are partially dietary in origin, such as creatine, creatinine, tricarboxylic acid (TCA) cycle intermediates, phenylacetylglycine, fumarate, glucose, taurine, fatty acids and N-methylnicotinamide, showed altered levels in the urine of treated and pair-fed animals. Many of these changes correlated well with weight loss. Interestingly, there was no increase in ketone bodies (acetate and β-hydroxybutyrate), which might be expected if energy metabolism was switched from glycolysis to fatty acid β-oxidation. In some instances, the metabolites that changed were consideredto be nonspecific markers of toxicity, but were also identified as markers of a specific type of toxicity. For example, taurine was raised significantly in carbon tetrachloride-treated animals but reduced in the pair-fed group. However, raised urinary bile acid levels were only seen after α -napthylisothiocyanate treatment. The methodology, statistical analysis used and the data generated will help improve the identification of specific markers or patterns of urinary markers of specific toxic effects.
KW - H-NMR
KW - Biomarker
KW - Feeding effects
KW - Hepatotoxicant
KW - Metabonomics
KW - Non-specific markers
KW - Weight loss
UR - http://www.scopus.com/inward/record.url?scp=4544326639&partnerID=8YFLogxK
U2 - 10.1080/13547500410001720767
DO - 10.1080/13547500410001720767
M3 - Article
C2 - 15370873
AN - SCOPUS:4544326639
SN - 1354-750X
VL - 9
SP - 156
EP - 179
JO - Biomarkers
JF - Biomarkers
IS - 2
ER -