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Comparison of 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated hepatotoxicity in C57BL/6J and DBA/2J mice
E S Shen1, S I Gutman, J R Olson
1Department of Pharmacology and Therapeutics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo 14214.
Abstract:
The toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was examined by clinical chemistry and liver histopathology in Ah-responsive C57BL/6J (C57) and Ah-nonresponsive DBA/2J (DBA) mice. Hepatotoxicity was assessed at 1, 3, and 7 d following a single ip injection of TCDD at doses that maximally induce hepatic aryl hydrocarbon hydroxylase (AHH) activity (3 micrograms/kg for C57 and 30 micrograms/kg for DBA mice) and at doses approaching the LD50 (150 micrograms/kg for C57 and 600 micrograms/kg for DBA mice). Histological examination of liver sections was found to be a more sensitive detection method for TCDD-induced hepatic changes than clinical chemistry analyses. Dramatic differences in the development and type of liver injury were observed between TCDD-treated C57 and DBA mice. C57 mice given 3 micrograms TCDD/kg developed mild to moderate hepatic lipid accumulation in the absence of both inflammation and necrosis. Severe fatty change and mild inflammation and necrosis occurred in C57 mice that received 150 micrograms TCDD/kg. In contrast, DBA mice exposed to 30 micrograms TCDD/kg developed hepatocellular necrosis and inflammation without any fatty change. Only slight hepatic lipid accumulation occurred with some necrosis and inflammation in DBA mice given 600 micrograms TCDD/kg. The Ah locus may play a role in determining the sensitivity of C57 mice to the steatotic effects of TCDD.
Insights
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes distinct liver injuries in mice, with Ah-responsive mice showing lipid accumulation and Ah-nonresponsive mice exhibiting necrosis. Histopathology is more sensitive than clinical chemistry for detecting TCDD toxicity.
Area of Science:
- Toxicology
- Hepatology
- Genetics
Background:
- 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent environmental toxicant.
- The Ah locus influences sensitivity to TCDD toxicity.
- Understanding TCDD-induced hepatotoxicity is crucial for risk assessment.
Purpose of the Study:
- To compare TCDD-induced hepatotoxicity in Ah-responsive (C57BL/6J) and Ah-nonresponsive (DBA/2J) mice.
- To evaluate the sensitivity of clinical chemistry versus liver histopathology in detecting TCDD effects.
- To investigate the role of the Ah locus in TCDD-mediated liver injury.
Main Methods:
- Single intraperitoneal injection of TCDD in C57BL/6J and DBA/2J mice at varying doses.
- Assessment of hepatotoxicity using clinical chemistry and liver histopathology at 1, 3, and 7 days post-injection.
- Quantification of hepatic aryl hydrocarbon hydroxylase (AHH) activity.
Main Results:
- Histopathology was more sensitive than clinical chemistry for detecting TCDD-induced liver changes.
- C57BL/6J mice showed dose-dependent lipid accumulation, with higher doses causing inflammation and necrosis.
- DBA/2J mice exhibited hepatocellular necrosis and inflammation, with minimal lipid accumulation, even at higher TCDD doses.
Conclusions:
- The Ah locus significantly influences the type and severity of TCDD-induced liver injury.
- Ah-responsive mice are more susceptible to TCDD-induced steatosis, while Ah-nonresponsive mice are prone to necrosis.
- Liver histopathology is a superior method for assessing TCDD-related hepatotoxicity.
