How great are the risks for children who ingest environmental toxins through breast feeding? Should Swedish people continue to eat fish caught in the Baltic Sea? These are questions to do with dioxins and are of the greatest importance for public health work in Sweden. In Sweden and Finland, we have a limited exemption from the EU prohibition to sell fish with dioxin levels in excess of the EU limit values in food. The fish must not be sold to other EU countries, not even as animal feed.
Fig. 2. Simplified sketch of Ah receptor activation by FICZ which is formed when the amino acid tryptophane is illuminated
Fig. 3. Penetration into skin of UVA (315-400 nm) and UVB (280-315 nm)
Knowledge of the mechanism of action of dioxins must be improved. One baffling problem is that after more than thirty years' of research we still do not understand the natural role of the protein, the Ah receptor (see the box) to which dioxins bind. Two research teams at Karolinska Institute and Stockholm University, with the support of Formas, are engaged on unique research with the focus on a new substance that is posited to be the natural ligand of the Ah receptor. There are great hopes that, with the help of this substance that is sometimes referred to as Vitamin F, it will be possible to clarify the physiological functions of the Ah receptor and thus increase knowledge of why dioxin-like compounds are so extremely toxic.
The question is which endogenous signal substance activates the Ah receptor and how it is formed. As early as 1987 we posited that substances which are formed when the amino acid tryptophan is illuminated are probably the natural signal substances of the Ah receptor. When, in 1995, we determined the chemical structure of the two most active substances (FICZ and dFICZ, see Fig. 1) it was clear that these represented a new type of substance. Work therefore commenced on the characterisation of these substances, their formation pathways, interactions with the Ah receptor and their biological decomposition pathways. Ultraviolet light (both UVB and UVA) and even visible light can mediate the formation of FICZ. Direct sunlight seems therefore to be capable of forming FICZ in the skin (Fig. 2 and 3) in the same way as vitamin D.
Fig. 4. The Ah receptor mediates the formation of melanin.
Vitamin F in humans
We have primarily focused the chemical analyses on identification of excretion products of FICZ in human urine. We will now carry out new analyses of FICZ since the processing methods devised for the persistent environmental pollutants of dioxin cannot be used for these non-persistent natural substances. We are therefore developing new online chemical methods for such analyses and are planning to take samples from people before and after light exposure in a solarium and from psoriasis patients treated with UV light.
Are there other similarities with vitamin D apart from formation via illumination? Can we even ingest vitamin F via food? Food products which contain tryptophan may also contain vitamin F if they are not protected from light. We are planning to analyse whether foods, mainly dairy products, contain vitamin F. For example, the formation of a closely related substance found in some varieties of cabbage has been demonstrated in the acid environment of the stomach of mice.
The role of the Ah receptor in the skin
It is problematic to use the most toxic dioxin, TCDD, as a model substance to form an idea of the physiological role of the Ah receptor. Above all, it has been found that TCDD causes overactivation of the functions of the Ah receptor and does not therefore give an accurate idea of the natural processes in which the receptor participates. As several other research teams all over the world, we are now using FICZ instead of TCDD as a model substance. We are working with different molecular techniques to analyse how FICZ affects the biological feedback systems, with the focus on the stability of the Ah receptor and its interactions with other factors which adapt the cell to changes in its environment. As regards physiological functions, we are mainly interested in the role of the Ah receptor in the skin, since FICZ is probably formed in the skin when it is illuminated. The skin after all is also a target organ for TCDD. In addition to chloracne, increased pigmentation is a phenomenon that has been observed in people exposed to dioxins. Smokers may also develop increased pigmentation on the gums and lips from compounds in tobacco smoke. We have studied whether the Ah receptor is involved in the formation of the pigment melanin in melanocytes, the pigment-producing cells in the skin (Fig. 4). We have found that both TCDD and FICZ activate the formation of melanin. We have also noted that FICZ stimulates the growth of skin cells and therefore seems able to activate the natural protection against UV light.
Many other pollutants we are exposed to in the external environment and the working environment, such as tobacco smoke and vehicle exhausts, also activate the Ah receptor. It is possible that its natural function is to adapt organisms to light and to mediate the protection against harmful UV light. One side effect is that chemical compounds that are similar to natural signal substances disrupt essential biological signal systems.
Ah (aryl hydrocarbon) receptor
There are groups of proteins (receptors) in somatic cells which have the ability to bind small endogenous signal molecules, e.g. hormones. The receptors mediate signals that activate certain genes and in this way adapt the cell to changes in its environment. The receptors can also bind exogenous substances that are similar to natural substances, and this results in hormone disrupting effects. One receptor which in its function is similar to a hormone receptor is the Ah receptor. The Ah receptor senses the presence of certain, both endogenous and exogenous, low-molecular chemical substances. It is best known for binding dioxin-like compounds and is therefore also called the dioxin receptor.
Persistent environmental pollutants. Binding to the Ah receptor is critical for the toxicity of dioxins. The most toxic dioxin, TCDD, decomposes in the body slowly and has a life of up to eight years in humans. In exposed people, TCDD and other similar compounds cause a serious form of acne, chloracne, and give rise to disruptions in foetal development. Damage to tooth enamel has for instance been seen in children exposed to TCDD as foetuses. In animals several serious toxic effects of TCDD have been identified, for example effects on the development of the immune system, nervous system and reproduction. These effects are manifested at levels close to those at which humans are exposed, primarily via food.
Natural signal substances. TCDD causes persistent stimulation of the Ah receptor and disrupts many integrated biological signal systems. This is clearly different from the short-lived activation that occurs with certain endogenous substances which are rapidly decomposed and excreted.
Author
:
Agneta Rannug
is professor at the Department of Environmental Medicine, Karolinska Institute
Ulf Rannug
is professor at the Department of Genetics, Microbiology and Toxicology, Stockholm University