Archives of Toxicology

, Volume 71, Issue 6, pp 372–382

Effect of subchronic 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on immune system and target gene responses in mice: calculation of benchmark doses for CYP1A1 and CYP1A2 related enzyme activities

  • Christoph Vogel
  • Susanne Donat
  • Olaf Döhr
  • Joachim Kremer
  • Charlotte Esser
  • Markus Roller
  • J. Abel
ORGAN TOXICITY AND MECHANISMS

DOI: 10.1007/s002040050401

Cite this article as:
Vogel, C., Donat, S., Döhr, O. et al. Arch Toxicol (1997) 71: 372. doi:10.1007/s002040050401

Abstract

The dose-effect relationships were analysed for several noncarcinogenic endpoints, such as immunological and biochemical responses at subchronic, low dose exposure of female C57BL/6 mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The animals were treated i.p. with TCDD according to the initial- and maintenance-dose principle for a period of 135 days. The initial doses were 1, 10 and 100 ng TCDD/kg, the weekly maintenance doses were 0.2, 2 and 20 ng TCDD/kg, respectively. At days 23, 79 and 135 of TCDD treatment 10 animals of each dose group were killed. As immunological parameters the number of thymocytes and the pattern of thymocyte subpopulations were determined. In liver, lung and thymus, mRNA expression of TGF-α, TGF-β1, TGF-β2, TGF-β3, TNF-α, IL-1β and different CYP1 isoforms (CYP1A1, CYP1A2, CYP1B1) was analysed. In the livers, activities of 7-ethoxyresorufin-O-deethylase (EROD) and 7-methoxyresorufin-O-demethylase (MROD) were measured. TCDD content in the liver was determined. The main results are summarized as follows: (1) The TCDD doses were not sufficient to elicit dose-dependent changes of pattern of thymocyte subpopulation. (2) TCDD failed to change the mRNA expression of TGF-α, TGF-β and TNF-α, but led to an increase of IL-1β mRNA expression in liver, lung and thymus. The results show that the TCDD induced IL-1β mRNA increase is at least as sensitive a marker as the induction of CYP1A isoforms. (3) The expression of CYP1B1 mRNA remained unchanged at the doses tested, while CYP1A1 and CYP1A2 mRNA expression was dose-dependently enhanced. EROD and MROD activities in the liver paralleled the increases of CYP1A1 and CYP1A2 mRNA expression. (4) Regression analysis of the data showed that most of the parameters tested fit a linear model. (5) From the data, a benchmark dose for EROD/MROD activities in the livers of female C57BL/6 mice of about 0.03 ng TCDD/kg per day was calculated.

Key words TCDD   Cytochrom P450   Cytokines    Immunesystem   Benchmark dose 

Copyright information

© Springer-Verlag Berlin Heidelberg 1997

Authors and Affiliations

  • Christoph Vogel
    • 1
  • Susanne Donat
    • 1
  • Olaf Döhr
    • 1
  • Joachim Kremer
    • 2
  • Charlotte Esser
    • 2
  • Markus Roller
    • 3
  • J. Abel
    • 1
  1. 1.Medical Institute of Environmental Hygiene at the Heinrich Heine University of Düsseldorf, Division of Toxicology, Auf'm Hennekamp 50, D-40225 Düsseldorf, GermanyDE
  2. 2.Medical Institute of Environmental Hygiene at the Heinrich Heine University of Düsseldorf, Division of Immunology Auf'm Hennekamp 50, D-40225 Düsseldorf, GermanyDE
  3. 3.Medical Institute of Environmental Hygiene at the Heinrich Heine University of Düsseldorf, Division of Experimental Hygiene Auf'm Hennekamp 50, D-40225 Düsseldorf, GermanyDE

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