Environmental Contaminant Mixtures at Ambient Concentrations Invoke a Metabolic Stress Response in Goldfish Not Predicted from Exposure to Individual Compounds Alone

Environmental contaminants from wastewater and industrial or agricultural areas are known to have adverse effects on development, reproduction, and metabolism. However, reliable assessment of environmental contaminant impact at low (i.e., ambient) concentrations using genomics and transcriptomics approaches has proven challenging. A goldfish model was used to investigate the effects of aquatic pollutant exposure in vivo by means of quantitative nuclear magnetic resonance metabolomics in multiple organs to elucidate a system-wide response. Animals were exposed to 4,4'-isopropylidenediphenol (Bisphenol-A, BPA), di-(2-ethylhexyl)-phthalate (DEHP), and nonylphenol (NP). Metabolite-specific spectral analysis combined with pathway-driven bioinformatics indicated changes in energy and lipid metabolism in liver following exposure to individual contaminants and a tertiary mixture. A dissimilar response in testis exposed to DEHP and mixture indicates disrupted AMPK and cAMP signaling. Uniquely, our observations (1) suggest that exposure to a contaminant mixture is characterized by a stress response not predicted from exposure to individual contaminants, even in the absence of other phenotypic features and (2) demonstrate the sensitivity of metabolomics in risk-assessment of environmental toxicant mixtures at ambient concentrations by detecting early stage metabolic dysregulation. These findings have general applicability in the assessment of benign compound mixtures in environmental and pharmaceutical development.