抄録
The exposome, an environmental analog of the genome, was originally introduced as a way to enhance environmental exposure assessment as it relates to epidemiology. However, the concept has evolved into one that provides a foundation for the analysis of complex environmental exposures to all of biology. This is especially apropos for the field of toxicology, which is striving to address the tens of thousands of chemicals that have received minimal analysis with regards to their toxicological impact. Dr. Miller will discuss the efforts at Emory University to develop an infrastructure to study the exposome and how these tools can be applied examine the toxicological consequences of complex exposures, including an example from Caenorhabditis elegans (C.elegans). Previous work has shown that disruption of the vesicular monoamine transporter 2 (VMAT2; SLC18A2) confers vulnerability to dopamine toxicity in mice and Parkinson’s disease in humans. The mutant cat-1 lacks the worm ortholog to VMAT2. We evaluated the effect of cat-1 deletion on lifespan using the hands-free, high-throughput Lifespan Machine, as developed by Stroustrup. We found that cat-1 mutants have an altered lifespan as compared to wild-type controls. In order to study the impact of exposures to complex chemical mixtures, we developed a high-throughput method to measure hundreds of exogenously applied chemical and subsequent metabolic products in the worms. Using three different high-resolution metabolomics platforms, the Agilent 6560 Ion Mobility Q-TOF LC/MS, the Thermo Q-Exactive HF LC/MS, and the Thermo Q Exactive GC hybrid quadrupole-Orbitrap GC-MS/MS, we are able to detect and quantify low levels of a wide variety of environmental chemicals (>350) representative of realistic exposures. These include polychlorinated biphenyls, brominated flame-retardants, organochlorine pesticides, phosphoester chemicals, herbicides, insecticides and pesticide synergists. Moreover, the combination of liquid chromatography (LC) and gas chromatography (GC) metabolomic platforms allows us additional measures of polar metabolites from environmental chemicals and endogenous metabolites (>5000). The high-resolution metabolomics platform can provide comprehensive coverage on as few as 100-1000 worms. The combination of genetically vulnerable mutants, the automated analysis of lifespan, and the high-resolution metabolomics analysis of endogenous and exogenous chemicals creates an ideal platform for studying gene-environment interactions at an exposome level.
