Mechanisms of Toxicity of Dioxins and Related Compounds

Dear Colleagues,

Dioxins have been subject to extensive research activity for the past half a century. It has become clear that these compounds are ubiquitous and persistent environmental contaminants, and that the group encompasses congeners with exceptionally high toxic potency, as exemplified by the model compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

The elucidation of the canonical AH receptor (AHR) signaling in the 1970s and 80s was a major breakthrough in our understanding of dioxin toxicity mechanisms. The present view is that an inappropriately intense and/or protracted activation of this signal transduction system constitutes the basis of most, if not all, major toxicities elicited by dioxins. However, the pathogenetic processes following AHR activation that eventually culminate in the well-described manifestations of dioxin exposure in laboratory animals have largely remained elusive – even to the extent that the critical target tissue for the acute toxicity of TCDD has yet to be established.

On the other hand, progress has been made in some subfields. In the last decade, the increasing interest of the scientific community in AHR’s physiological functions has simultaneously helped advance the elucidation of dioxin action mechanisms. This is because TCDD has been one of the most common AHR activators employed. TCDD has also been exploited as a potent pharmacological tool in studies aimed at shedding light on insufficiently understood physiological or pathological phenomena. Consequently, novel information has been gained on the interference of dioxins with the immune system (e.g., autoimmune reactions), reproductive organs, and liver functions (steatohepatitis).

A Special Issue devoted to dioxin toxicity mechanisms in the International Journal of Molecular Sciences is thus timely and well-grounded. All manuscripts furthering our current understanding on how dioxins impart their adverse health effects are welcome, be they based on in vivo or in vitro experiments. Of particular interest would be studies on impacts mediated by alternative, non-canonical signaling pathways, or by epigenetic mechanisms. As mentioned above, there is still a notable data gap of biochemical steps between AHR-mediated gene regulation and toxic signs. At the cellular or tissue level, some intriguing topics would be the effects of dioxins on stem cells and on the central nervous system. Mechanistic explanations for the wide differences in sensitivities to dioxin toxicity, both among and within species, are further called for. More information is also needed on the mechanisms of dioxin carcinogenicity.

Dr. Raimo Pohjanvirta
Guest Editor

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