Toxicology in the Fast Lane: Application of High-Throughput Bioassays to Detect Modulation of Key Enzymes and Receptors

Details

• Alternative Title:
  Environ Health Perspect
• Personal Author:
  Morisseau, Christophe ; Merzlikin, Oleg ; Lin, Amy ; He, Guochun ; Feng, Wei ; Padilla, Isela ; Denison, Michael S. ; Pessah, Isaac N. ; Hammock, Bruce D.
• Description:
  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.
  
  
• Subjects:
  Animals Bioassays Biomarkers Carboxylesterase Enzyme Inhibition High-throughput Assays High-Throughput Screening Assays Humans Naphthoquinones Receptors, Androgen Receptors, Aryl Hydrocarbon Receptors, Estrogen Research Ryanodine Receptor Calcium Release Channel Toxicology Triclocarban Triclosan

  More +
• Source:
  Environ Health Perspect. 2009; 117(12):1867-1872.
• Pubmed ID:
  20049205
• Pubmed Central ID:
  PMC2799460
• Document Type:
  Journal Article
• Funding:
  1P01 ES11269/ES/NIEHS NIH HHS/United States ; P42 ES004699/ES/NIEHS NIH HHS/United States ; P42 ES04699/ES/NIEHS NIH HHS/United States ; R01 ES013933/ES/NIEHS NIH HHS/United States ; R01ES012498/ES/NIEHS NIH HHS/United States ; R01ES014901/ES/NIEHS NIH HHS/United States ; R01ES02710/ES/NIEHS NIH HHS/United States ; U50 OH07550/OH/NIOSH CDC HHS/United States
• Volume:
  117
• Issue:
  12
• NIOSHTIC Number:
  nn:20036317
• Collection(s):
  CDC Public Access National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:3e6bfcc9b01fa50633e5153153cc3045b362ef17fc4a3dbd7a13425d87de1b6c14596bd576ff53f1747187017c260cbfb43d01c6173ee16a34f04c898d97cc70
• Download URL:
  https://stacks.cdc.gov/view/cdc/22928/cdc_22928_DS1.pdf
• File Type:
  [PDF - 911.47 KB ]