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. Topdown 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. Keywords: metabonomics, cadmium, environmental health, exposome, metabolomics, molecular epidemiolog

Associations between Urinary Excretion of Cadmium and Proteins in a Nonsmoking Population: Renal Toxicity or Normal Physiology?

BACKGROUND: Associations between cadmium (Cd) and kidney function have been reported even at low levels of exposure in the general population. Recently, the causality of these associations has been questioned. OBJECTIVES: We examined associations between urinary Cd (U-Cd; a biomarker of exposure) and urinary proteins that are used as biomarkers of kidney effects, based on repeated short-term sampling in healthy subjects. METHODS: Twenty-four hour urine samples were collected on 2 separate days at six fixed times from 30 healthy nonsmoking men and women (median age 39 years). We analyzed the samples (N = 354) for Cd (i.e., U-Cd) and two proteins used as kidney function biomarkers: urinary albumin (U-Alb) and alpha-1-microglobulin (U-A1M). Concentrations were adjusted for creatinine concentration or for specific gravity, and excretion rates (mass per hour) were calculated. Possible associations were assessed within each individual participant, and mean correlations and regressions were evaluated. RESULTS: We found clear positive mean associations within individuals between the excretion of U-Cd [mean, 0.11 mu g/g creatinine (range, 0.01-0.52 mu g/g creatinine)] and both U-Alb and U-A1M. The associations were stronger for excretion rates and concentrations adjusted for specific gravity than for concentrations adjusted for creatinine. We also found significant positive associations of urinary flow with excretion of U-Cd, U-Alb, and U-A1M. CONCLUSIONS: Associations between short-term changes in U-Cd and markers of kidney function within individual nonsmoking study participants are unlikely to reflect effects of Cd toxicity. A more likely explanation is that these associations result from normal variation in renal function, including changes in urinary flow, that influence the urinary excretion of both Cd and proteins in the same direction. These effects of normal variability may result in overestimation of the adverse effects of Cd on kidney function at low-level Cd exposure