This research project aims to shed more light on the mechanisms of action of dioxin toxicity and certain physiological effects of the AH receptor. TCDD (2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin) is used as the model compound for the dioxin group. It is the most potent derivative of the group and the most toxic synthetic compound known. In short, these are the central research objectives of the project:
(1) To investigate, with the help of DNA methylation analysis, whether TCDD can cause hereditary epigenetic changes in rats.
(2) To investigate, with the help of proteomics, transcriptomics, metabolomics and lipidomics, the metabolic changes in rats caused by TCDD.
(3) To verify the AHR-mediated nature of a peculiar behavioural effect, namely the avoidance of new feed, seen earlier in connection with TCDD, and to investigate its connection with a similar, previously known behavioural model, conditioned taste aversion.
(4) To determine the toxicity profiles of two new selective AHR modulators in vivo and in vitro. Selective AHR modulators activate the receptor but do not cause the same adverse effects as dioxins. Thus, they are potential candidates for drug development.
(5) To test whether AHR knockout rats are resistant to obesity caused by a high-fat diet the same way AHR knockout mice are.
(6) To find out to what extent the AH receptor participates in regulating the circadian rhythm in rats. All prior studies focused on the physiological connection of the AH receptor to circadian rhythms have been conducted with mice, which makes verification of the generalisability of results a priority.
To achieve these objectives, the project uses a commercial strain of AHR knockout rats, as well as a large number of samples collected earlier from two rat strains with more than a thousand-fold difference in their TCDD-sensitivity. The most important cooperation partners of the project are the Ontario Institute for Cancer Research in Toronto, Canada (Dr Paul Boutros), the National University of Singapore (Dr Krishna Chaithanya Batchu) and the toxicology laboratory at the National Institute for Health and Welfare in Finland (Docent Matti Viluksela).
The previous dioxin research project, led by Professor Pohjanvirta, was part of the Centre for Environmental Health Risk Analysis of the National Public Health Institute in 2002–2007.