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Gene expression dose-response of liver with a genotoxic and nongenotoxic carcinogen

Shawn D Seidel1, William T Stott, H Lynn Kan

  • 1Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674, USA. sseidel2@dow.com

International Journal of Toxicology
|March 3, 2006
PubMed

Insights

This study investigated how genotoxic and nongenotoxic carcinogens affect gene expression in rat livers. Results show distinct transcriptional responses, with higher doses potentially leading to adaptation or toxicity, altering gene expression patterns.

Area of Science:

  • Toxicology and Molecular Biology
  • Environmental Health Sciences

Background:

  • Chemical carcinogens induce tumors via genotoxic or nongenotoxic mechanisms.
  • Nongenotoxic tumorigenesis pathways are less understood than genotoxic ones.
  • Gene expression changes (transcriptome) offer insights into cellular responses to carcinogens.

Purpose of the Study:

  • To elucidate dose-response gene expression alterations in rat liver following exposure to a genotoxic (AAF) and a nongenotoxic (PB) carcinogen.
  • To compare the transcriptomic profiles induced by different modes of chemical carcinogenesis.
  • To investigate atypical dose-response relationships in gene expression.

Main Methods:

  • Male Big Blue Fischer 344 rats were administered varying doses of 2-acetylaminofluorene (AAF) or phenobarbital (PB) for 28 days.
  • Transcriptome analysis was conducted using the Clontech Rat Toxicology II microarray (465 genes).
  • Gene expression levels were quantified by hybridizing 32P-labeled cDNA targets.

Main Results:

  • AAF altered 14 genes (9 up, 5 down); PB altered 18 genes (10 up, 8 down).
  • Four genes showed common alterations (2 up, 2 down) between AAF and PB treatments.
  • Atypical dose-response patterns were observed, with higher doses sometimes resembling control levels, suggesting adaptation, toxicity, or remodeling.

Conclusions:

  • Both genotoxic and nongenotoxic carcinogens induce specific, yet partially overlapping, transcriptional changes in the liver.
  • Gene expression responses to toxic agents can exhibit complex dose-dependent patterns, deviating from simple linear relationships.
  • Understanding these transcriptional dynamics is crucial for characterizing chemical carcinogenesis and risk assessment.

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