Discovery of Metabolic Signatures for Predicting Whole Organism Toxicology

Abstract

Toxicological studies in sentinel organisms frequently use biomarkers to assess biological effect. Development of "omic" technologies has enhanced biomarker discovery at the molecular level, providing signatures unique to toxicant mode-of-action (MOA). However, these signatures often lack relevance to organismal responses, such as growth or reproduction, limiting their value for environmental monitoring. Our primary objective was to discover metabolic signatures in chemically exposed organisms that can predict physiological toxicity. Marine mussels (Mytilus edulis) were exposed for 7 days to 12 and 50 microg/l copper and 50 and 350 microg/l pentachlorophenol (PCP), toxicants with unique MOAs. Physiological responses comprised an established measure of organism energetic fitness, scope for growth (SFG). Metabolic fingerprints were measured in the same individuals using nuclear magnetic resonance-based metabolomics. Metabolic signatures predictive of SFG were sought using optimal variable selection strategies and multivariate regression and then tested upon independently field-sampled mussels from rural and industrialized sites. Copper and PCP induced rational metabolic and physiological changes. Measured and predicted SFG were highly correlated for copper (r(2) = 0.55, P = 2.82 x 10(-7)) and PCP (r(2) = 0.66, P = 3.20 x 10(-6)). Predictive metabolites included methionine and arginine/phosphoarginine for copper and allantoin, valine, and methionine for PCP. When tested on field-sampled animals, metabolic signatures predicted considerably reduced fitness of mussels from the contaminated (SFG = 6.0 J/h/g) versus rural (SFG = 15.2 J/h/g) site. We report the first successful discovery of metabolic signatures in chemically exposed environmental organisms that inform on molecular MOA and that can predict physiological toxicity. This could have far-reaching implications for monitoring impacts on environmental health.

Gas chromatography time-of-flight mass spectrometry based metabolomic approach to evaluating toxicity of triptolide

“…Because low-molecular-weight compounds are the endpoints of metabolism and systemic functions, their in vivo levels reflect the physiological and biochemical status of the organism. Thus, their measurement has the potential to evaluate the toxicity, identify the toxic markers or organ-specific markers, and explore the metabolism-related mechanism (Nicholson et al 2002;Robertson 2005;Keun 2006; Schnackenberg and Beger 2008;Griffin and Bollard 2004;Beger et al 2010;Andreadou et al 2009;Clarke and Haselden 2008;Collings and Vaidya 2008;Hines et al 2010;Goodsaid et al 2009;Boudonck et al 2009). Although dozens of metabolomcis/ metabonomics studies have been conducted to explore toxicity and achieved fruitful results (reviewed by Beger et al 2010;Schnackenberg and Beger 2008;Robertson 2005;Keun 2006; Griffin and Bollard 2004;Collings and Vaidya 2008;Ebbels et al 2007;Clarke and Haselden 2008;Nicholson et al 2002), few of them have associated the routine toxicity data with those from metabolomics studies both in qualitative and quantitative ways.…”

Applications of biological tools or biomarkers in aquatic biota: A case study of the Tamar estuary, South West England

“…Such an approach has many benefits, including the potential for earlier warning, the detection of chronic effects, and increased mechanistic understanding of adverse outcomes ( Fig. 2; Fedorenkova et al, 2010;Hines et al, 2010). In particular, alterations in transcriptional gene expression (i.e.…”

Proteomic research in bivalves

“…Subsequently, metabolomic studies in mussels were mainly addressed to discriminate and understand the mode of action of pesticides like atrazine and lindane [94], pentachlorophenol [95] and metals like copper and cadmium [95,96].…”