Toxicology in the fast lane: application of high-throughput bioassays to detect modulation of key enzymes and receptors.
Morisseau-C; Merzlikin-O; Lin-A; He-G; Feng-W; Padilla-I; Denison-MS; Pessah-IN; Hammock-BD
Environ Health Perspect 2009 Dec; 117(12):1867-1872
BACKGROUND: Legislation at state, federal, and international levels is requiring rapid evaluation of the toxicity of numerous chemicals. Whole-animal toxicologic studies cannot yield the necessary throughput in a cost-effective fashion, leading to a critical need for a faster and more cost-effective toxicologic evaluation of xenobiotics. OBJECTIVES: We tested whether mechanistically based screening assays can rapidly provide information on the potential for compounds to affect key enzymes and receptor targets, thus identifying those compounds requiring further in-depth analysis. METHODS: A library of 176 synthetic chemicals was prepared and examined in a high-throughput screening (HTS) manner using nine enzyme-based and five receptor-based bioassays. RESULTS: All the assays have high Z' values, indicating good discrimination among compounds in a reliable fashion, and thus are suitable for HTS assays. On average, three positive hits were obtained per assay. Although we identified compounds that were previously shown to inhibit a particular enzyme class or receptor, we surprisingly discovered that triclosan, a microbiocide present in personal care products, inhibits carboxylesterases and that dichlone, a fungicide, strongly inhibits the ryanodine receptors. CONCLUSIONS: Considering the need to rapidly screen tens of thousands of anthropogenic compounds, our study shows the feasibility of using combined HTS assays as a novel approach toward obtaining toxicologic data on numerous biological end points. The HTS assay approach is very useful to quickly identify potentially hazardous compounds and to prioritize them for further in-depth studies.
Bioassays; Biochemical-analysis; Biochemical-tests; Biocides; Biological-effects; Biological-monitoring; Chemical-composition; Chemical-hypersensitivity; Chemical-properties; Chemical-reactions; Exposure-assessment; Exposure-levels; Exposure-methods; Microbiology; Microchemistry; Microscopic-analysis; Toxic-effects; Toxicology;
Author Keywords: bioassays; biomarkers; enzyme inhibition; high throughput assays; triclocarban; triclosan
Christophe Morisseau, Department of Entomology, One Shields Avenue, University of California, Davis, CA 95616
Agriculture; Cooperative Agreement
Environmental Health Perspectives
University of California - Davis