Raimo Pohjanvirta's research group

Research in food and environmental toxicology

Research in the discipline focuses mostly on one significant group of environmental contaminants: dioxins. Even though it is by its nature basic research into the molecular impact mechanism of these substances as well as the toxicological characteristics and physiological duties of the protein transmitting their effects, the findings simultaneously serve the risk assessment of dioxins and other similarly functioning chemicals.

AH receptor as a mediator of toxicity and regulator of physiological processes of the body

Dioxins are environmental contaminants present all over the world that, already in extremely small exposure doses, cause an exceptionally large variety of various biochemical and toxic responses in experimental animals. They accumulate in the food chain and their elimination half-life in humans is very long (several years). Epidemiological evidence has been found on their potential connection to, for example, diabetes, effects related to reproductive organs and the thyroid gland, cardiovascular diseases and changes in the onset of puberty, as well as cognitive disorders in humans. On these grounds, dioxins are still considered one of the most significant groups of toxicants, even though their background concentrations have reduced markedly in the last 30 years.

Despite dioxins being among the most thoroughly studied contaminant chemicals in the world, their mechanisms of toxicity are still not fully known. What is known, however, is that a molecular initiating event apparently critical to all significant adverse effects caused by dioxins is their binding to an intracellular protein known as the AH (aryl hydrocarbon) receptor. This AH receptor is a transcription factor that is activated when ligands, such as dioxins, bind with it and, consequently, changes the expression of the genes it regulates. The AH receptor is a well-conserved, over 600-million-year-old protein molecule whose physiological effects have only recently begun to be unmasked. Among other things, it has been proven to be essential for the development of intraepithelial lymphocytes in the intestinal tract and skin. In addition, the receptor regulates the balance between Th17 and Treg cells and, thus, their susceptibility to autoimmune reactions. By studying AHR knockout mice, the receptor has been found to have a role in regulating the growth of several organs and tissues, stem cell differentiation, circadian rhythm adaptation and the maintenance of disease tolerance. The latest finding is a connection to the development of obesity caused by a high-fat diet.

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.