Induction of CYP1A1 in Primary Rat Hepatocytes by 3,3′, 4,4′, 5-Pentachlorobiphenyl: Evidence for a Switch Circuit Element

Details

• Personal Author:
  Andersen ME ; Billings RE ; Chubb LS ; French CT ; Hanneman WH
• Description:
  In vivo induction of CYP1A1 in hepatocytes by aryl hydrocarbon receptor agonists is heterogeneous. Using immunohistochemistry, cells appear to be either induced or not induced as if the response of an individual cell is better represented as a switch. We have examined induction of CYP1A1 in vitro in primary rat hepatocytes to distinguish the responses of populations of cells and responses of individual cells. Cells were treated with various concentrations of the aryl hydrocarbon receptor agonist, 3,3',4,4',5-pentachlorobiphenyl. Concentration-response and time-course responses were determined for the population of cells by Western blotting for CYP1A1 protein and by real-time RT-PCR for CYP1A1 mRNA. Individual cell responses were visualized by immunocytochemistry (ICC) for protein and by in situ hybridization (ISH) for mRNA. CYP1A1 mRNA was quantified by frequency distribution analysis of grains observed on the ISH slides. Population responses showed time- and concentration-related increases in induction. Single cell responses appeared as all-or-none in the field, with cells appearing to be induced and others appearing to be not induced. Even at the highest concentrations (2.5 x 10(-7) M), some hepatocytes remained unresponsive. Distribution frequencies of single cell induction were more consistent with a switch with variable levels of induction in cells depending on treatment concentration. Combined with the reports from in vivo studies, our results support a switch with rheostat behavior for individual hepatocytes. Mechanistic studies in liver cell lines that are confirmed to exhibit switch-like induction of single cells will be necessary to assess the molecular pathways of this circuit element. [Description provided by NIOSH]
• Subjects:
  Animals Cell Division Cells, Cultured Chemistry Communicable Diseases Dioxins Hypersensitivity Liver Occupational Health Risk Assessment Risk Factors Safety

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• Keywords:
  Animal-studies Author Keywords: Polychlorinated Biphenyl Cell-alteration Cell-biology Cell-cultures Cell-damage Cell-division Cell-function Cell-metabolism Cell-migration Cell-transformation Cellular-function Cellular-reactions Chemical-analysis Chemical-hypersensitivity Chemical-indicators Chemical-properties Chemical-reactions Chemical-structure Chemical-synthesis CYP1A1 Dioxides Exposure-levels Exposure-limits Exposure-methods Hepatic-microsomal-enzymes Hepatitis Hepatocytes Hepatotoxicity Hepatotoxins Risk-analysis Risk-factors

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• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  Colorado ; OSHA Region 8
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  276-286
• Volume:
  78
• Issue:
  2
• NIOSHTIC Number:
  nn:20035337
• Citation:
  Toxicol Sci 2004 Apr; 78(2):276-286
• Contact Point Address:
  C. T. French, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523
• Email:
  Hanneman@colostate.edu
• Federal Fiscal Year:
  2004
• Performing Organization:
  Colorado State University - Fort Collins
• Peer Reviewed:
  True
• Start Date:
  20010930
• Source Full Name:
  Toxicological Sciences
• End Date:
  20030929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:88c5d4ce5375c9aecb7d1b6fde1b35fa02bce4508c06946933fa9939cb705f80ce206fb5eded4f4babd492df1b4c1dac9bd5c7e726dc594177fdd6bff78539c2
• Download URL:
  https://stacks.cdc.gov/view/cdc/187235/cdc_187235_DS1.pdf
• File Type:
  [PDF - 512.34 KB ]