Aryl hydrocarbon receptor agonists trigger avoidance of novel food in rats

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of dioxins, but also plays important physiological roles, which are only beginning to unfold. Previous studies have surprisingly unveiled that low doses of the potent AHR agonist TCDD induce a strong and persistent avoidance of novel food items in rats. Here, we further examined the involvement of the AHR in the avoidance response in Sprague-Dawley rats with three established AHR agonists: 6-formylindolo(3,2-b)carbazole (FICZ), β-naphthoflavone (BNF) and benzo[a]pyrene (BaP); with a novel selective AHR modulator (C2); and with an activator of another nuclear receptor, CAR: 2,4,6-tryphenyldioxane-1,3 (TPD). As sensitive indices of AHR or CAR activity, we used Cyp1a1 and Cyp2b1 gene expression, as they are, respectively, the drug-metabolizing enzymes specifically regulated by them. We further attempted to address the roles played by enhanced neophobia and conditioned taste aversion (CTA) in the avoidance behaviour. All AHR agonists triggered practically total avoidance of novel chocolate, but the durations varied. Likewise, acutely subtoxic doses of C2, differing by 25-fold, all elicited a similar outcome. In contrast, TPD did not influence chocolate consumption at all. If rats were initially accustomed to chocolate for 6h after single FICZ or BNF exposure, avoidance was still clearly present two weeks later when chocolate was offered again. Hence, the avoidance response appears to specifically involve the AHR instead of being triggered by induction of intestinal or hepatic nuclear receptor signalling in general. It is also shared by both endogenous and exogenous AHR activators. Moreover, this behavioural change in rats seems to contain elements of both CTA and enhanced neophobia, but further clarification of this is still required.

Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats

“…thymic atrophy, changes in tissue retinoid (vitamin A) concentrations and, as we previously reported for C2, novel food avoidance (Fletcher, et al 2001, Harris, et al 1973, Lensu, et al 2011a, Mahiout and Pohjanvirta 2016, Tuomisto, et al 2000. Thymic atrophy is one of the most consistent and uniform effects of TCDD across mammalian species .…”

“…8). Moreover, in our previous in vivo study, even a single dose of 4 mg/kg C2 induced hepatic Cyp1a1 expression 1700-fold compared with controls, when liver was sampled already at 28 h after exposure (Mahiout and Pohjanvirta 2016). Collectively, these findings imply a rapid and probably inducible elimination of C2 and C4 in S-D rats, with an elimination half-life within a range of hours to a couple of days for repeated exposure.…”

Chemistry and Properties of Indolocarbazoles

“…When 100 μg FICZ kg −1 was administered to Sprague− Dawley rats by gavage, it triggered practically total avoidance of novel chocolate and the avoidance was still clearly present 2 weeks later when chocolate was offered again. 483 FICZ Activates Nuclear Hormone Receptors. FICZ has also been found to activate receptors belonging to the superfamily of nuclear hormone receptors including vertebrate vitamin D receptors, the invertebrate pregnane X receptor, invertebrate, and vertebrate liver X receptors (LXRs) including the human LXRα and LXRβ, as well as peroxisome proliferator-activated receptors (PPARs).…”

Transgenerational epigenetic and transcriptomic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure in rat

“…Despite the absence of physiological changes in testes from previous studies (Manikkam et al 2012a), we detected numerous DMRs within this tissue. In our study, a conspicuous finding was that olfactory receptors seemed to be frequently affected by differential methylation; this in itself is quite interesting as a highly sensitive behavioral response to AHR agonists is aversion to novel foodstuffs (Lensu et al 2011a;Mahiout and Pohjanvirta 2016), and this may involve the sense of smell. Differential methylation of Olr60 was also reported by Manikkam et al, albeit in a different tissue type (sperm rather than testis) (Manikkam et al 2012b).…”