Related Experiment Videos
Do new hypotheses on the mechanism of action of dioxins help in risk evaluation?
1Department of Environmental Hygiene and Toxicology, National Public Health Institute, Kuopio, Finland.
Abstract:
The mechanism of action of chlorinated dibenzodioxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is not known, but the prevailing hypothesis is the binding to a specific protein, the Ah-receptor, and subsequent alteration of the expression of specific genes. This Ah-receptor hypothesis does not explain all aspects of toxicity, notably the extreme variation of toxicity between different animal species. We have found two rat strains that differ widely in their sensitivity to TCDD. The resistant Han/Wistar (H/W) rat tolerates doses up to 3000 micrograms kg-1, while 20 micrograms kg-1 is lethal to Long-Evans (L-E) rats. Several morphological, biochemical and endocrinological parameters as well as pharmacokinetics have been screened, but the strains behave by and large similarly. However, there is a clear behavioural difference: TCDD causes anorexia in both strains, but H/W rats start eating again in 1-2 weeks, whereas the reduction of feed intake is permanent in L-E rats until they die in about 3 weeks. Han/Wistar rats, which recover after a single large dose of TCDD, behave aberrantly for months; they seem to have a supersensitive satiety response while they do not respond normally to energy deficiency. Therefore the regulation of feed intake or of body weight seem to be altered permanently by TCDD. It is also of interest that TCDD is more toxic after a central than after a peripheral administration. These findings may be of importance for the risk evaluation of dioxins, because they might help to explain the wide species/strain variation which complicates the assessment of dioxin risk to humans.
Insights
TCDD toxicity varies greatly between rat strains, with Long-Evans rats succumbing to low doses while Han/Wistar rats recover. This suggests TCDD permanently alters feed intake regulation, impacting dioxin risk assessment.
Area of Science:
- Toxicology
- Environmental Health
- Neuroscience
Background:
- The precise mechanism of action for chlorinated dibenzodioxins, like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), remains unclear.
- The prevailing Ah-receptor hypothesis does not fully account for the significant interspecies toxicity variations observed.
Purpose of the Study:
- To investigate the mechanism of TCDD toxicity and explain inter-species variations.
- To identify the factors contributing to differential sensitivity to TCDD in different animal strains.
Main Methods:
- Comparative study using two rat strains with differing TCDD sensitivity: Han/Wistar (resistant) and Long-Evans (sensitive).
- Screening of morphological, biochemical, endocrinological, and pharmacokinetic parameters.
- Detailed behavioral observation focusing on feed intake and recovery patterns post-TCDD exposure.
Main Results:
- Han/Wistar rats tolerated 3000 µg/kg TCDD, while Long-Evans rats died at 20 µg/kg.
- A key difference observed was TCDD-induced anorexia; Han/Wistar rats recovered feed intake in 1-2 weeks, whereas Long-Evans rats exhibited permanent anorexia.
- Recovered Han/Wistar rats displayed persistent behavioral alterations, including altered satiety responses and energy deficiency response, suggesting permanent changes in feed intake regulation.
Conclusions:
- TCDD exposure can lead to permanent alterations in feed intake and body weight regulation, independent of the Ah-receptor pathway.
- Observed behavioral differences and differential recovery rates between rat strains may explain the wide species/strain variation in dioxin toxicity.
- Findings have implications for human risk assessment of dioxins, particularly regarding species-specific responses.