Exploring the toxicological and physiological functions of the AH receptor: Selective modulation by two novel compounds and involvement in novel food avoidance behaviour

Selma Mahiout

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

The aim of this thesis study was to gain more information on the physiological and toxicological functions of the aryl hydrocarbon receptor (AHR). The effects of two novel selective AHR modulators (SAHRMs) were investigated in vitro and in vivo. In addition, the involvement of the AHR in the avoidance of novel food was examined.

The AHR is an evolutionarily ancient, apparently over 600-million-year-old protein. It is a ligand-activated transcription factor that modulates the expression of various genes within cells. One of the most studied groups of compounds that activate the AHR are dioxins. They are environmental contaminants primarily formed as by-products of various industrial processes, and many of them are toxic. Dioxins are chemically very persistent and lipid soluble, and thus accumulate in the food chain. Therefore, humans are also exposed to small amounts from food. In Finland, the most common source of dioxins is fatty wild fish from the Baltic Sea.

The AHR has been recognised as the mediator of dioxin-induced toxicity for decades. More recently, it has also been shown to be involved in several physiological functions of the body, including the regulation of reproduction, foetal development, the immune system and autoimmunity. However, our understanding of the mechanisms of both the toxicological and physiological functions of the AHR remains incomplete. As a consequence, for instance, human health risk assessment of dioxins is challenging. Furthermore, better understanding of the physiological effects of the AHR could help elucidate the aetiology and pathogenesis of certain diseases, and therefore also benefit the discovery of novel pharmacological therapies.

As lead compounds for drug discovery, SAHRMs are particularly interesting. They only elicit subsets of AHR-mediated effects, often without the major toxic outcomes of dioxins. Moreover, they could be valuable tools in elucidating the so far incompetently understood, multifaceted physiological roles of AHR, and the underlying molecular mechanisms.

This thesis research had two main objectives. The first was related to studying the in vitro and in vivo toxicity of two novel SAHRMs, which are intended as drug compounds for the treatment of autoimmune diseases. The aim was to determine whether they appear suitable for pharmacological use from the pre-clinical safety perspective. Furthermore, finding out the extent to which their effects resemble or differ from those of the most toxic dioxin, TCDD, was of interest. The second objective was to accumulate more knowledge on a peculiar novel food avoidance behaviour, previously characterised in rats and mice after exposure to TCDD. This behaviour resembles a recognised behaviour model, conditioned taste aversion (CTA), which is also exhibited in humans, for instance in conjunction with nausea related to cancer treatment. The aim here was to verify whether the aforementioned rodent response is a physiological effect of the AHR or, more specifically, a consequence of TCDD exposure.

Based on the results, the novel SAHRMs are very effective AHR activators, both in vitro and in vivo, and are in fact comparable to TCDD. However, their toxicity profiles are distinct from that of TCDD, and they appear considerably less toxic in rats. Therefore, the novel SAHRMs appear promising as possible drug compounds, and also highly interesting as tools for AHR research. Despite the differences in toxicity, one of the novel SAHRMs, as well as all of the three other AHR activators tested in this study, induced a strong avoidance response resembling that previously observed to TCDD, but shorter lasting. In addition, the reaction was not inducible in AHR knock-out rats. Thus, this study confirmed that the novel food avoidance behaviour is mediated by the AHR. The effect appears protective against potentially harmful ingested foods, and is therefore another physiological function of the AHR.
Original languageEnglish
Supervisors/Advisors
  • Pohjanvirta, Raimo, Supervisor
Award date9 May 2018
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-4217-7
Electronic ISBNs978-951-51-4218-4
Publication statusPublished - 2018
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 413 Veterinary science
  • Toxicology

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