+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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

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

Archives of Toxicology 71(6): 372-382

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 principal 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/kg, 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-alpha, TGF-beta(1), TGF-beta(2), TGF-beta(3), TNF-alpha, IL-1 beta 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-alpha, TGF-beta and TNF-alpha, but led to an increase of IL-1 beta mRNA expression in liver, lung and thymus. The results show that the TCDD induced IL-1 beta 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.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 008547555

Download citation: RISBibTeXText

PMID: 9195019

DOI: 10.1007/s002040050401

Related references

Dose-Response Relationships in Mice Following Subchronic Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin: CYP1A1, CYP1A2, Estrogen Receptor, and Protein Tyrosine Phosphorylation. Toxicology and Applied Pharmacology 124(1): 82-90, 1994

Dose-response relationships of tissue distribution and induction of CYP1A1 and CYP1A2 enzymatic activities following acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Toxicology and Applied Pharmacology 130(2): 197-208, 1995

Dose-response relationships for induction of CYP1A1 and CYP1A2 enzyme activity in liver, lung, and skin in female mice following subchronic exposure to polychlorinated biphenyls. Toxicology and Applied Pharmacology 167(3): 157-172, 2000

Pulmonary CYP1A1 and CYP1A2 levels and activities in adult male and female offspring of rats exposed during gestation and lactation to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochemical Pharmacology 62(5): 617-626, 1 September, 2001

Characterization of the dose-response of CYP1B1, CYP1A1, and CYP1A2 in the liver of female Sprague-Dawley rats following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology and Applied Pharmacology 154(3): 279-286, 1999

Dose-response relationships for chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in a rat tumor promotion model: quantification and immunolocalization of CYP1A1 and CYP1A2 in the liver. Cancer Research 52(12): 3436-3442, 1992

Disposition of 2,3,7,8-tetrabromodibenzo-p-dioxin and 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat: biliary excretion and induction of cytochromes CYP1A1 and CYP1A2. Toxicology and Applied Pharmacology 111(1): 163-172, 1991

Transcriptional activation of avian CYP1A4 and CYP1A5 by 2,3,7, 8-tetrachlorodibenzo-p-dioxin: differences in gene expression and regulation compared to mammalian CYP1A1 and CYP1A2. Toxicology and Applied Pharmacology 155(1): 96, 1999

Theophylline pharmacokinetics: comparison of Cyp1a1(-/-) and Cyp1a2(-/-) knockout mice, humanized hCYP1A1_1A2 knock-in mice lacking either the mouse Cyp1a1 or Cyp1a2 gene, and Cyp1(+/+) wild-type mice. Pharmacogenetics and Genomics 15(7): 503-511, 2005

Altered operant responding for motor reinforcement and the determination of benchmark doses following perinatal exposure to low-level 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environmental Health Perspectives 109(6): 621-627, 2001

Interindividual variability of CYP1A1 and CYP1A2 in human livers and induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin in vitro. FASEB Journal 7(7): A1167, 1993

Sensitivity of CYP1A1 mRNA inducibility by dioxin is the same in Cyp1a2(+/+) wild-type and Cyp1a2(-/-) null mutant mice. Biochemical Pharmacology 54(10): 1127-1131, 1997

2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated oxidative stress in CYP1A2 knockout (CYP1A2-/-) mice. Biochemical and Biophysical Research Communications 264(2): 376-379, 1999

Use of CYP1A2 knockout and CYP1A2 C57BL/6N parental strains of mice to compare metabolism of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin. Toxicological Sciences 72(S-1): 363, 2003

Hepatic gene downregulation following acute and subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicological Sciences 94(2): 428-438, 2006