Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population.
BACKGROUND
The 'exposome' represents the accumulation of all environmental exposures across a lifetime. Top-down strategies are required to assess something this comprehensive, and could transform our understanding of how environmental factors affect human health. Metabolic profiling (metabonomics/metabolomics) defines an individual's metabolic phenotype, which is influenced by genotype, diet, lifestyle, health and xenobiotic exposure, and could also reveal intermediate biomarkers for disease risk that reflect adaptive response to exposure. We investigated changes in metabolism in volunteers living near a point source of environmental pollution: a closed zinc smelter with associated elevated levels of environmental cadmium.


METHODS
High-resolution ¹H NMR spectroscopy (metabonomics) was used to acquire urinary metabolic profiles from 178 human volunteers. The spectral data were subjected to multivariate and univariate analysis to identify metabolites that were correlated with lifestyle or biological factors. Urinary levels of 8-oxo-deoxyguanosine were also measured, using mass spectrometry, as a marker of systemic oxidative stress.


RESULTS
Six urinary metabolites, either associated with mitochondrial metabolism (citrate, 3-hydroxyisovalerate, 4-deoxy-erythronic acid) or one-carbon metabolism (dimethylglycine, creatinine, creatine), were associated with cadmium exposure. In particular, citrate levels retained a significant correlation to urinary cadmium and smoking status after controlling for age and sex. Oxidative stress (as determined by urinary 8-oxo-deoxyguanosine levels) was elevated in individuals with high cadmium exposure, supporting the hypothesis that heavy metal accumulation was causing mitochondrial dysfunction.


CONCLUSIONS
This study shows evidence that an NMR-based metabolic profiling study in an uncontrolled human population is capable of identifying intermediate biomarkers of response to toxicants at true environmental concentrations, paving the way for exposome research.
Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington, London, SW7 2AZ, UK.
James K
JK
Ellis
Toby J
TJ
Athersuch
Laura D K
LD
Thomas
Friederike
F
Teichert
Miriam
M
Pérez-Trujillo
Claus
C
Svendsen
David J
DJ
Spurgeon
Rajinder
R
Singh
Lars
L
Järup
Jacob G
JG
Bundy
Hector C
HC
Keun
D000080242:8-Hydroxy-2'-Deoxyguanosine; D015415:Biomarkers / Q000652:urine; D002104:Cadmium / Q000633:toxicity*; D019343:Citric Acid / Q000652:urine; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D004781:Environmental Exposure; D059647:Gene-Environment Interaction; D006801:Humans; D008019:Life Style; D009682:Magnetic Resonance Spectroscopy; D055432:Metabolomics; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress
D015415:Biomarkers; D002104:Cadmium; D019343:Citric Acid; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine