Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population

BackgroundThe '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.MethodsHigh-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.ResultsSix 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.ConclusionsThis 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.

[1]  Stephen M Rappaport,et al.  Environment and Disease Risks , 2010, Science.

[2]  M. Webber,et al.  Tumor Suppressor Gene Inactivation during Cadmium-Induced Malignant Transformation of Human Prostate Cells Correlates with Overexpression of de Novo DNA Methyltransferase , 2007, Environmental health perspectives.

[3]  Ian J. Brown,et al.  Human metabolic phenotype diversity and its association with diet and blood pressure , 2008, Nature.

[4]  C. Wild,et al.  Environmental exposure measurement in cancer epidemiology. , 2008, Mutagenesis.

[5]  P. Brandt,et al.  Evaluation of certain food additives. Joint FAO/WHO Expert Committee on Food Additives. Fifty-ninth report of the JECFA, nitrate and nitrite , 2002 .

[6]  Jack A. Taylor,et al.  Cadmium is a mutagen that acts by inhibiting mismatch repair , 2003, Nature Genetics.

[7]  Paolo Vineis,et al.  Meeting-in-the-middle using metabolic profiling – a strategy for the identification of intermediate biomarkers in cohort studies , 2011, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[8]  B. Kågedal,et al.  beta 2-Microglobulinuria among workers previously exposed to cadmium: follow-up and dose-response analyses. , 1985, American journal of industrial medicine.

[9]  C. Wild.  Complementing the Genome with an “Exposome”: The Outstanding Challenge of Environmental Exposure Measurement in Molecular Epidemiology , 2005, Cancer Epidemiology Biomarkers & Prevention.

[10]  Seon-Hee Oh,et al.  A rapid and transient ROS generation by cadmium triggers apoptosis via caspase-dependent pathway in HepG2 cells and this is inhibited through N-acetylcysteine-mediated catalase upregulation. , 2006, Toxicology and applied pharmacology.

[11]  J. Nicholson,et al.  The initial pathogenesis of cadmium induced renal toxicity , 2000, FEBS letters.

[12]  M. Wieckowski,et al.  Mitochondria as an important target in heavy metal toxicity in rat hepatoma AS-30D cells. , 2008, Toxicology and applied pharmacology.

[13]  P J Sadler,et al.  Quantitative high resolution 1H NMR urinalysis studies on the biochemical effects of cadmium in the rat. , 1989, Molecular pharmacology.

[14]  L. Teppo,et al.  Health effects of cadmium exposure - a review of the literature and a risk estimate , 1998 .

[15]  Caroline O Odewumi,et al.  Mechanism of DNA damage by cadmium and interplay of antioxidant enzymes and agents , 2007, Environmental toxicology.

[16]  Josef Schlatter,et al.  Evaluation of certain food additives and contaminants. , 2013, World Health Organization technical report series.

[17]  B. Kågedal,et al.  Assessment of renal function in workers previously exposed to cadmium. , 1985, British journal of industrial medicine.

[18]  B. Katzenellenbogen,et al.  Activation of estrogen receptor-alpha by the heavy metal cadmium. , 2000, Molecular endocrinology.

[19]  Zhiwei Liu,et al.  Rapid activation of ERK1/2 and AKT in human breast cancer cells by cadmium. , 2008, Toxicology and applied pharmacology.

[20]  M. Evans,et al.  Oxidative DNA damage and disease: induction, repair and significance. , 2004, Mutation research.

[21]  Susan Hodgson,et al.  Early Kidney Damage in a Population Exposed to Cadmium and Other Heavy Metals , 2008, Environmental health perspectives.

[22]  M. Arnal,et al.  Assessment of threonine metabolism in vivo by gas chromatography/mass spectrometry and stable isotope infusion. , 1991, Analytical biochemistry.

[23]  A. J. Shaka,et al.  Water Suppression That Works. Excitation Sculpting Using Arbitrary Wave-Forms and Pulsed-Field Gradients , 1995 .

[24]  P. Møller,et al.  Biomarkers of oxidative damage to DNA and repair. , 2008, Biochemical Society transactions.

[25]  S. Skerfving,et al.  Tubular and Glomerular Kidney Effects in Swedish Women with Low Environmental Cadmium Exposure , 2005, Environmental health perspectives.

[26]  L Järup,et al.  Health effects of cadmium exposure--a review of the literature and a risk estimate. , 1998, Scandinavian journal of work, environment & health.

[27]  D. Gauguier,et al.  Statistical total correlation spectroscopy: an exploratory approach for latent biomarker identification from metabolic 1H NMR data sets. , 2005, Analytical chemistry.

[28]  Shizhen Song,et al.  Effects of long-term low-dose cadmium exposure on genomic DNA methylation in human embryo lung fibroblast cells. , 2008, Toxicology.

[29]  L. Hamm.  Renal handling of citrate. , 1990, Kidney international.

[30]  Ò. Miró,et al.  Smoking disturbs mitochondrial respiratory chain function and enhances lipid peroxidation on human circulating lymphocytes. , 1999, Carcinogenesis.

[31]  James K. Ellis,et al.  Outdoor and indoor cadmium distributions near an abandoned smelting works and their relations to human exposure. , 2011, Environmental pollution.

[32]  J. Huff,et al.  Cadmium-induced Cancers in Animals and in Humans , 2007, International journal of occupational and environmental health.

[33]  J. Griffin,et al.  Metabolic profiling of chronic cadmium exposure in the rat. , 2001, Chemical research in toxicology.

[34]  J. Lindon,et al.  NMR-based metabolic profiling and metabonomic approaches to problems in molecular toxicology. , 2008, Chemical research in toxicology.

[35]  J. Lindon,et al.  'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. , 1999, Xenobiotica; the fate of foreign compounds in biological systems.

[36]  J. Nicholson,et al.  Cadmium and mercury nephrotoxicity , 1983, Nature.

[37]  D. Bleyl,et al.  IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs vol. 1 to 42. Supplement 7. 440 Seiten. International Agency for Research on Cancer, Lyon 1987. Preis: 65, – s.Fr , 1989 .

[38]  J. Mellon,et al.  Determination of 8-oxo-2'-deoxyguanosine and creatinine in murine and human urine by liquid chromatography/tandem mass spectrometry: application to chemoprevention studies. , 2009, Rapid communications in mass spectrometry : RCM.

[39]  Paolo Vineis,et al.  Molecular Epidemiology and Biomarkers in Etiologic Cancer Research: The New in Light of the Old , 2007, Cancer Epidemiology Biomarkers & Prevention.

[40]  J. Nriagu,et al.  Quantitative assessment of worldwide contamination of air, water and soils by trace metals , 1988, Nature.

[41]  D. Groneberg,et al.  Journal of Occupational Medicine and Toxicology the Toxicity of Cadmium and Resulting Hazards for Human Health , 2006 .

[42]  J. Richmond,et al.  Measurement of vitamin D3 metabolites in smelter workers exposed to lead and cadmium. , 1998, Occupational and environmental medicine.

[43]  Ò. Miró,et al.  Effect of Smoking Cessation on Mitochondrial Respiratory Chain Function , 2003, Journal of toxicology. Clinical toxicology.

[44]  B. Katzenellenbogen,et al.  Activation of Estrogen Receptor-α by the Heavy Metal Cadmium , 2000 .

[45]  J. Lindon,et al.  Metabonomics: a platform for studying drug toxicity and gene function , 2002, Nature Reviews Drug Discovery.

[46]  W. Ko,et al.  Mediating of caspase‐independent apoptosis by cadmium through the mitochondria‐ROS pathway in MRC‐5 fibroblasts , 2004, Journal of cellular biochemistry.

[47]  J. Nriagu.  A silent epidemic of environmental metal poisoning? , 1988, Environmental pollution.

[48]  V. Cogliano.  International Agency for Research on Cancer (IARC) , 2018, The Grants Register 2019.

[49]  Exposures in the glass manufacturing industry. , 1993, IARC monographs on the evaluation of carcinogenic risks to humans.

[50]  M. Waalkes,et al.  Repeated cadmium exposures enhance the malignant progression of ensuing tumors in rats. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[51]  B. Trock,et al.  Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland , 2003, Nature Medicine.

[52]  L Järup,et al.  Low level exposure to cadmium and early kidney damage: the OSCAR study , 2000, Occupational and environmental medicine.

[53]  O Axelson,et al.  Cadmium exposure and end-stage renal disease. , 2001, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[54]  Lars Järup,et al.  Current status of cadmium as an environmental health problem. , 2009, Toxicology and applied pharmacology.

[55]  H. Senn,et al.  Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in 1H NMR metabonomics. , 2006, Analytical chemistry.

[56]  T. Fan.  Metabolite profiling by one- and two-dimensional NMR analysis of complex mixtures , 1996 .

[57]  H. Keun,et al.  Metabonomic modeling of drug toxicity. , 2006, Pharmacology & therapeutics.

[58]  Daniel Raftery,et al.  Identification of 4-deoxythreonic acid present in human urine using HPLC and NMR techniques. , 2009, Journal of pharmaceutical and biomedical analysis.