Search

Background: Obesity is increasingly taking an important stage as a cause of death worldwide, and interventions with a good cost‐effectiveness ratio are needed. Psychotria densinervia is one of these natural products with health benefits. Objective. The present study evaluated the cytotoxicity, antiadipogenic, low‐density lipoprotein (LDL), oxidation inhibitory activities, and acute toxicity of Psychotria densinervia hydroethanolic leaf and bark extracts. Methods: The cytotoxicity evaluation of the extracts (62.5, 125, 250, and 500 μg/mL) using the MTT assay and the antiadipogenic activity (25, 50, 100, and 200 μg/mL) using oleic acid were carried out in SW‐872 cells. Copper sulfate (CuSO4)‐induced oxidation was used in the evaluation of the effect of extracts (0.25, 0.5, and 1 mg/mL) against LDL oxidation. The oral acute toxicity evaluation of a single dose of 2000 mg/kg of the extracts was performed in Wistar albino rats weighing 127 ± 2 g. Results: The leaf and bark extracts did not show any sign of cytotoxicity at the tested concentrations. The best antiadipogenic activity was observed by the standard orlistat (38.45 ± 1.70 μg/mL), followed by the leaf extract (IC50: 41.47 ± 0.50 μg/mL) and the least the bark extract (IC50: 107.50 ± 0.90 μg/mL). At a concentration of 1 mg/mL, the leaf extract presented an oxidation lag time of 130 min, which was higher and better than that of the bark extract (120 min). Quercetin (standard) presented an oxidation lag time longer than 3 h. The oral acute toxicity evaluation did not show any signs of toxicity indicating that the LD50 was greater than 2000 mg/kg. Conclusion: Based on the results obtained, the P. densinervia hydroethanolic leaf extract possesses a better antioxidant and antiadipogenic activities than the bark extract. [ABSTRACT FROM AUTHOR]

Background: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent congener of the dioxin class of environmental contaminants. Exposure to TCDD causes a wide range of toxic outcomes, ranging from chloracne to acute lethality. The severity of toxicity is highly dependent on the aryl hydrocarbon receptor (AHR). Binding of TCDD to the AHR leads to changes in transcription of numerous genes. Studies evaluating the transcriptional changes brought on by TCDD may provide valuable insight into the role of the AHR in human health and disease. We therefore compiled a collection of transcriptomic datasets that can be used to aid the scientific community in better understanding the transcriptional effects of ligand-activated AHR. Results: Specifically, we have created a datasets package -TCDD.Transcriptomics - for the R statistical environment, consisting of 63 unique experiments comprising 377 samples, including various combinations of 3 species (human derived cell lines, mouse and rat), 4 tissue types (liver, kidney, white adipose tissue and hypothalamus) and a wide range of TCDD exposure times and doses. These datasets have been fully standardized using consistent preprocessing and annotation packages (available as of September 14, 2015). To demonstrate the utility of this R package, a subset of "AHR-core" genes were evaluated across the included datasets. Ahrr, Nqo1 and members of the Cyp family were significantly induced following exposure to TCDD across the studies as expected while Aldh3a1 was induced specifically in rat liver. Inmt was altered only in liver tissue and primarily by rat-AHR. Conclusions: Analysis of the "AHR-core" genes demonstrates a continued need for studies surrounding the impact of AHR-activity on the transcriptome; genes believed to be consistently regulated by ligand-activated AHR show surprisingly little overlap across species and tissues. Until now, a comprehensive assessment of the transcriptome across these studies was challenging due to differences in array platforms, processing methods and annotation versions. We believe that this package, which is freely available for download (http://labs.oicr.on.ca/boutros-lab/tcddtranscriptomics) will prove to be a highly beneficial resource to the scientific community evaluating the effects of TCDD exposure as well as the variety of functions of the AHR. [ABSTRACT FROM AUTHOR]

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 6 h 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. [ABSTRACT FROM AUTHOR]

In haem degradation, haem oxygenase-1 ( HO-1) first cleaves haem to biliverdin, which is reduced to bilirubin by biliverdin IXα reductase ( BVR- A). The environmental pollutant 2,3,7,8-tetrachlorodibenzo- p-dioxin ( TCDD) causes hepatic accumulation of biliverdin in moderately TCDD-resistant line B ( Kuopio) rats. Using line B and two TCDD-sensitive rat strains, the present study set out to probe the dose-response and biochemical mechanisms of this accumulation. At 28 days after exposure to 3-300 μg/kg TCDD in line B rats, already the lowest dose of TCDD tested, 3 μg/kg, affected serum bilirubin conjugates, and after doses ≥100 μg/kg, the liver content of bilirubin, biliverdin and their conjugates (collectively 'bile pigments') as well as HO-1 was elevated. BVR- A activity and serum bile acids were increased only by the doses of 100 and 300 μg/kg TCDD, respectively. Biliverdin conjugates correlated best with biliverdin suggesting it to be their immediate precursor. TCDD (100 μg/kg, 10 days) increased hepatic bilirubin and biliverdin levels also in TCDD-sensitive Long- Evans ( Turku/ AB; L- E) rats. Hepatic bilirubin and bile acids, but not biliverdin, were increased in feed-restricted L- E control rats. In TCDD-sensitive line C ( Kuopio) rats, 10 μg/kg of TCDD increased the body-weight-normalized biliary excretion of bilirubin. Altogether, the results suggest that at acutely toxic doses, TCDD induces the formation of bilirubin in rats. However, concurrently, TCDD seems to hamper the quantitative conversion of biliverdin to bilirubin in line B and L- E rats' liver. Biliverdin conjugates are most likely formed as secondary products of biliverdin. [ABSTRACT FROM AUTHOR]

Basal divergences in circadian feeding and drinking patterns among different rat strains may bias comparative physiological and pharmacological studies. To examine this issue in detail, Long-Evans (Turku/AB) (L-E) and Han/Wistar (Kuopio) (H/W) rats were monitored with an automated system for seven consecutive days after a habituation period. For the analysis, days were split into hours or into four diurnal periods, and the chronologically repetitive nature of the data was taken into account. While L-E rats displayed two distinct peaks in feeding and drinking that coincided with the light shifts, H/W rats exhibited their lowest consummatory activity at the morning light shift. Further differences were recorded in a number of variables including numbers of meals and drinking episodes as well as their durations. These findings reveal surprisingly wide inter-strain differences. Hence, one should be careful in generalizing ingestive behavioural data obtained from a single rat strain to the entire species. [ABSTRACT FROM AUTHOR]

Rat is a major model organism in toxicogenomics and pharmacogenomics. Hepatic mRNA profiles after treatment with xenobiotic chemicals are used to predict and understand drug toxicity and mechanisms. Surprisingly, neither inter- and intra-strain variability of mRNA abundances in control rats nor the heritability of rat mRNA abundances yet been established. We address these issues by studying five populations: the popular Sprague-Dawley strain, sub-strains of Long-Evans and Wistar rats, and two lines derived from crosses between the Long-Evans and Wistar sub-strains. Using three independent techniques - variance analysis, linear modelling, and unsupervised pattern recognition - we characterize extensive intraand inter-strain variability in mRNA levels. We find that both sources of variability are non-random and are enriched for specific functional groups. Specific transcription-factor binding-sites are enriched in their promoter regions and these genes occur in ''islands'' scattered throughout the rat genome. Using the two lines generated by crossbreeding we tested heritability of hepatic mRNA levels: the majority of rat genes appear to exhibit directional genetics, with only a few interacting loci. Finally, a comparison of inter-strain heterogeneity between mouse and rat orthologs shows more heterogeneity in rats than mice; thus rat and mouse heterogeneity are uncorrelated. Our results establish that control hepatic mRNA levels are relatively homogeneous within rat strains but highly variable between strains. This variability may be related to increased activity of specific transcription-factors and has clear functional consequences. Future studies may take advantage of this phenomenon by surveying panels of rat strains. [ABSTRACT FROM AUTHOR]

Abstract: Han/Wistar (Kuopio; H/W) rats are exceptionally resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity mainly because of their mutated aryl hydrocarbon receptor (AHR) gene. In H/W rats, altered splicing of the AHR mRNA generates two AHR proteins: deletion (DEL) and insertion (INS) variants, with the INS isoform being predominantly expressed. To gain further insight into their functional properties, cDNAs of these and rat wild-type (rWT) isoform were transferred into C57BL/6J-derived mice by microinjection. The endogenous mouse AHR was eliminated by selective crossing with Ahr-null mice. A single mouse line was obtained for each of the three constructs. The AHR mRNA levels in tissues were generally close to those of C57BL/6 mice in INS and DEL mice and somewhat higher in rWT mice; in testis, however, all 3 constructs exhibited marked overexpression. The transgenic mouse lines were phenotypically normal except for increased testis weight. Induction of drug-metabolizing enzymes by TCDD occurred similarly to that in C57BL/6 mice, but there tended to be a correlation with AHR concentrations, especially in testis. In contrast to C57BL/6 mice, the transgenics did not display any major gender difference in susceptibility to the acute lethality and hepatotoxicity of TCDD; rWT mice were highly sensitive, DEL mice moderately resistant and INS mice highly resistant. Co-expression of mouse AHR and rWT resulted in augmented sensitivity to TCDD and abolished the natural resistance of female C57BL/6 mice, whereas mice co-expressing mouse AHR and INS were resistant. Thus, these transgenic mouse lines provide a novel promising tool for molecular studies on dioxin toxicity and AHR function. [Copyright &y& Elsevier]

Background: Mouse and rat models are mainstays in pharmacology, toxicology and drug development -- but differences between strains and between species complicate data interpretation and application to human health. Dioxin-like polyhalogenated aromatic hydrocarbons represent a major class of environmentally and economically relevant toxicants. In mammals dioxin exposure leads to a broad spectrum of adverse affects, including hepatotoxicity of varying severity. Several studies have shown that dioxins extensively alter hepatic mRNA levels. Surprisingly, though, analysis of a limited portion of the transcriptome revealed that rat and mouse responses diverge greatly (Boverhof et al. Toxicol Sci 94:398-416, 2006). Results: We employed oligonucleotide arrays to compare the response of 8,125 rat and mouse orthologs. We confirmed that there is limited inter-species overlap in dioxin-responsive genes. Rat-specific and mouse-specific genes are enriched for specific functional groups which differ between species, conceivably accounting for species-specificities in liver histopathology. While no evidence for the involvement of copy-number variation was found, extensive inter-species variation in the transcriptional-regulatory network was identified; Nr2f1 and Fos emerged as candidates to explain species-specific and species-independent responses, respectively. Conclusion: Our results suggest that a small core of genes is responsible for mediating the similar features of dioxin hepatotoxicity in rats and mice but non-overlapping pathways are simultaneously at play to result in distinctive histopathological outcomes. The extreme divergence between mouse and rat transcriptomic responses appears to reflect divergent transcriptional-regulatory networks. Taken together, these data suggest that both rat and mouse models should be used to screen the acute hepatotoxic effects of drugs and toxic compounds. [ABSTRACT FROM AUTHOR]

The environmental toxicant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) causes multiple effects in laboratory animals. One of these is a wasting syndrome (a dramatic loss of body weight over 2–5 weeks) whose mechanism is still largely unknown. We exploited the over 1000 times difference in TCDD sensitivity between Long-Evans ( Turku/AB); (L-E) and Han/Wistar ( Kuopio); (H/W) rats to reveal brain areas that might be activated by a single dose of TCDD (50 μg/kg) given 24 hr previously. Leptin (1.3 mg/kg intraperitoneally 2 hr before tissue harvest) was used as a reference compound, as its neural pathway for decreasing food intake in the control of energy homeostasis is fairly well known. Serial sections of the brains were immunostained with an antibody for the activity marker c-Fos, and selected areas – primarily in the hypothalamus – were analysed with a computer-assisted microscope. Given alone, TCDD did not elicit any major alterations in c-Fos protein levels in the hypothalamic nuclei at the early time-point studied (24 hr after administration), neither in pooled data nor in individual strains. The control substance leptin proved that the method is valid as it increased the number of c-Fos-immunopositive cells in the hypothalamic ventromedial and arcuate nuclei. Although the present findings are not suggestive of a primary role for the hypothalamus in the wasting syndrome, a time-course study covering also the feeding-active dark hours is warranted for their verification. [ABSTRACT FROM AUTHOR]

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread, persistent, and highly toxic environmental pollutant. The most TCDD-sensitive and the most TCDD-resistant rat strains (Long-Evans [Turku/AB] and Han/Wistar [Kuopio], respectively) were crossbred to separate the alleles of two genes (Ahrand an unidentified gene “B”) mediating resistance against TCDD toxicity. During crossbreeding, a new type of toxicity in livers of both sexes was detected, characterized macroscopically by intense dark green to black color and swelling that appeared most frequently after a large dose (300 μg/kg or more as a single intragastric dose) and a follow-up period of more than three weeks. Therefore, studies were undertaken to identify the causative pigment chemically and to examine the hepatotoxicity histologically. The pigment fractions were separated by thin layer chromatography and then analyzed by HPLC and electrospray mass spectrometry. The pigment was found to consist of biliverdin and several biliverdin-related compounds. In liver histopathology carried out on male rats, progressive sinusoidal distension and hepatic peliosis with membrane-bound cysts were seen. The clinical manifestations of pigment accumulation were recorded most often in intermediately resistant rat lines such as line B (homozygous for the geneB), but never occurred in rats expressing only the Han/Wistar (Kuopio)-type Ah receptor with an altered transactivation domain structure. [ABSTRACT FROM PUBLISHER]

The aryl hydrocarbon receptor repressor (AHRR) is a negative regulator of AH receptor (AHR), which mediates most of the toxic and biochemical effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AHR has been shown to be the major reason for the exceptionally wide (ca. 1000-fold) sensitivity difference in acute toxicity of TCDD between two rat strains, sensitive Long–Evans (Turku/AB) (L–E) and resistant Han/Wistar (Kuopio) (H/W), but there is another, currently unknown contributing factor involved. In the present study, we examined AHRR structure and expression in these rat strains to find out whether AHRR could be this auxiliary factor. Molecular cloning of AHRR coding region showed that consistent with AHRR proteins in other species, the N-terminal end of rat AHRR is highly conserved, but PAS B and Q-rich domains are severely truncated or lacking. Identical structures were recorded in both strains. Next, the time-, dose-, and tissue-dependent expression of AHRR was determined using quantitative real-time RT-PCR. In liver, AHRR expression was very low in untreated rats, but it increased rapidly after TCDD exposure (100 μg/kg). Testis exhibited the highest constitutive expression of AHRR, whereas kidney, spleen, and heart showed the highest induction of AHRR in response to TCDD treatment. Again, no marked differences were found between H/W and L–E rats, implying that AHRR is not the auxiliary contributing factor to the strain difference in TCDD sensitivity. However, simultaneous measurement of CYP1A1 mRNA reinforced the view that AHRR is an important determinant of tissue-specific responsiveness to TCDD. [Copyright &y& Elsevier]

The aryl hydrocarbon receptor (AHR) mediates the toxicity of dioxins, but also plays important physiological roles. Selective AHR modulators, which elicit some effects imparted by this receptor without causing the marked toxicity of dioxins, are presently under intense scrutiny. Two novel such compounds are IMA-08401 ( N-acetyl-N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide ) and IMA-07101 ( N-acetyl-N- ( 4-trifluoromethylphenyl ) -4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide ). They represent, as diacetyl prodrugs, AHR-active metabolites of the drug compounds laquinimod and tasquinimod, respectively, which are intended for the treatment of autoimmune diseases and cancer. Here, we toxicologically assessed the novel compounds in Sprague-Dawley rats, after a single dose (8.75–92.5 mg/kg) and 5-day repeated dosing at the highest doses achievable (IMA-08401: 100 mg/kg/day; and IMA-07101: 75 mg/kg/day). There were no overt clinical signs of toxicity, but body weight gain was marginally retarded, and the treatments induced minimal hepatic extramedullary haematopoiesis. Further, both the absolute and relative weights of the thymus were significantly decreased. Cyp1a1 gene expression was substantially increased in all tissues examined. The hepatic induction profile of other AHR battery genes was distinct from that caused by 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). The only marked alterations in serum clinical chemistry variables were a reduction in triglycerides and an increase in 3-hydroxybutyrate. Liver and kidney retinol and retinyl palmitate concentrations were affected largely in the same manner as reported for TCDD. In vitro , the novel compounds activated CYP1A1 effectively in H4IIE cells. Altogether, these novel compounds appear to act as potent activators of the AHR, but lack some major characteristic toxicities of dioxins. They therefore represent promising new selective AHR modulators. [ABSTRACT FROM AUTHOR]

Polychlorinated dibenzodioxins are environmental contaminants commonly produced as a by-product of industrial processes. The most potent of these, 2,3,7,8-tetrachlorodibenzo- ρ -dioxin (TCDD), is highly lipophilic, leading to bioaccumulation. White adipose tissue (WAT) is a major site for energy storage, and is one of the organs in which TCDD accumulates. In laboratory animals, exposure to TCDD causes numerous metabolic abnormalities, including a wasting syndrome. We therefore investigated the molecular effects of TCDD exposure on WAT by profiling the transcriptomic response of WAT to 100 μg/kg of TCDD at 1 or 4 days in TCDD-sensitive Long-Evans ( Turku/AB ; L-E) rats. A comparative analysis was conducted simultaneously in identically treated TCDD-resistant Han/Wistar ( Kuopio ; H/W) rats one day after exposure to the same dose. We sought to identify transcriptomic changes coinciding with the onset of toxicity, while gaining additional insight into later responses. More transcriptional responses to TCDD were observed at 4 days than at 1 day post-exposure, suggesting WAT shows mostly secondary responses. Two classic AHR-regulated genes, Cyp1a1 and Nqo1 , were significantly induced by TCDD in both strains, while several genes involved in the immune response, including Ms4a7 and F13a1 were altered in L-E rats alone. We compared genes affected by TCDD in rat WAT and human adipose cells, and observed little overlap. Interestingly, very few genes involved in lipid metabolism exhibited altered expression levels despite the pronounced lipid mobilization from peripheral fat pads by TCDD in L-E rats. Of these genes, the lipolysis-associated Lpin1 was induced slightly over 2-fold in L-E rat WAT on day 4. [ABSTRACT FROM AUTHOR]

In some mammals, halogenated aromatic hydrocarbon (HAH) exposure causes wasting syndrome, defined as significant weight loss associated with lethal outcomes. The most potent HAH in causing wasting is 2,3,7,8-tetrachlorodibenzo- ρ -dioxin (TCDD), which exerts its toxic effects through the aryl hydrocarbon receptor (AHR). Since TCDD toxicity is thought to predominantly arise from dysregulation of AHR-transcribed genes, it was hypothesized that wasting syndrome is a result of to TCDD-induced dysregulation of genes involved in regulation of food-intake. As the hypothalamus is the central nervous systems' regulatory center for food-intake and energy balance. Therefore, mRNA abundances in hypothalamic tissue from two rat strains with widely differing sensitivities to TCDD-induced wasting syndrome: TCDD-sensitive Long–Evans rats and TCDD-resistant Han/Wistar rats, 23 h after exposure to TCDD (100 μg/kg) or corn oil vehicle. TCDD exposure caused minimal transcriptional dysregulation in the hypothalamus, with only 6 genes significantly altered in Long–Evans rats and 15 genes in Han/Wistar rats. Two of the most dysregulated genes were Cyp1a1 and Nqo1, which are induced by TCDD across a wide range of tissues and are considered sensitive markers of TCDD exposure. The minimal response of the hypothalamic transcriptome to a lethal dose of TCDD at an early time-point suggests that the hypothalamus is not the predominant site of initial events leading to hypophagia and associated wasting. TCDD may affect feeding behaviour via events upstream or downstream of the hypothalamus, and further work is required to evaluate this at the level of individual hypothalamic nuclei and subregions. [ABSTRACT FROM AUTHOR]

Abstract: Despite several decades of research, the complete mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other xenobiotic agonists of the aryl hydrocarbon receptor (AHR) cause toxicity remains unclear. While it has been shown that the AHR is required for all major manifestations of toxicity, the specific downstream changes involved in the development of toxic phenotypes remain unknown. Here we examine a panel of 13 genes that are AHR-regulated in many species and tissues. We profiled their hepatic mRNA abundances in two rat strains with very different sensitivities to TCDD: the TCDD-sensitive Long–Evans (Turku/AB; L–E) and the TCDD-resistant Han/Wistar (Kuopio; H/W). We evaluated doses ranging from 0 to 3000μg/kg at 19h after TCDD exposure and time points ranging from 1.5 to 384h after exposure to 100μg/kg TCDD. Twelve of 13 genes responded to TCDD in at least one strain, and seven of these showed statistically significant inter-strain differences in the time course analysis (Aldh3a1, Cyp1a2, Cyp1b1, Cyp2a1, Fmo1, Nfe2l2 and Nqo1). Cyp2s1 did not respond to TCDD in either rat strain. Five genes exhibited biphasic responses to TCDD insult (Ahrr, Aldh3a1, Cyp1b1, Nfe2l2 and Nqo1), suggesting a secondary event, such as association with additional transcriptional modulators. Of the 12 genes that responded to TCDD during the dose–response analysis, none had an ED50 equivalent to that of Cyp1a1, the most sensitive gene in this study, while nine genes responded to doses at least 10–100 fold higher, in at least one strain (Ahrr (L–E), Aldh3a1 (both), Cyp1a2 (both), Cyp1b1 (both), Cyp2a1 (L–E), Inmt (both), Nfe2l2 (L–E), Nqo1 (L–E) and Tiparp (both)). These data shed new light on the association of the AHR target genes with TCDD toxicity, and in particular the seven genes exhibiting strain-specific differences represent strong candidate mediators of Type-II toxicities. [Copyright &y& Elsevier]

Abstract: In rats, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes anorexia that may lead to fatal wasting but has hitherto been poorly characterized. Therefore, we studied in-depth feeding and drinking behaviors of TCDD-sensitive L–E rats for 5 (100μg/kg; lethal dose) or 10 (10μg/kg; sublethal) days and of TCDD-resistant H/W rats for 14 (100 or 1000μg/kg; both sublethal) days postexposure to TCDD. The 1000-fold higher resistance of H/W rats to acute lethality of TCDD results from a mutation in their AH receptor (AHR). We split days into four (morning, daytime, evening, and night) or two (light/dark) circadian periods and took the repeated nature of the data into account. In L–E rats at 100μg/kg, the feed intake dropped precipitously, due to reduced meal sizes. In H/W rats, the hypophagia remained moderate and stemmed from a reduced meal frequency. While the suppression in L–E rats peaked during the morning (at 100μg/kg), the main effects in H/W rats were seen during the constant light or dark phases. Furthermore, chronologic data analysis revealed alterations in consecutive feeding and drinking patterns. Thus, striking differences were found between these strains in the timing and structure of consummatory behaviors, suggesting involvement of the AHR in these behaviors. [Copyright &y& Elsevier]

Abstract: A conspicuous but scantly studied feature of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity is avoidance of unfamiliar foodstuffs, which seems to be one of the very few exquisitely sensitive behavioural effects in adult laboratory animals. Here we characterized this peculiar response further after low doses of TCDD. The time-course of the novelty avoidance, the role of nutriment form and dependence of the aversion on the time lag between TCDD exposure and the presentation of a novel food item was determined using rats with different sensitivities to lethality of TCDD. Rats were offered chocolate, liquid nutriment or familiar feed with an unfamiliar texture and the consumptions were measured for varying periods. Aversion to a novel food item (chocolate) emerged within 5.5h after TCDD exposure. A lag of a week or more between TCDD exposure and the presentation of chocolate abolished the avoidance whereas simultaneous presentation of chocolate with TCDD treatment rendered the rats oblivious to the chocolate''s presence for over 40 days. Rats avoided also liquid nutriments when these were coupled with TCDD administration but this faded much sooner than chocolate aversion. Even a change in feed texture at the exposure was able to elicit the response. However, habituation was found to interfere with the aversion. These findings indicate that temporal proximity to TCDD exposure is a requisite for the avoidance response which emerges rapidly and may linger on for extended periods, but is not strictly confined to any specific food type. The molecular mechanisms of this tantalizing behavioural alteration remain to be determined. [Copyright &y& Elsevier]

Abstract: The dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic effects in rodent species, all of which are mediated by a ligand-dependent transcription-factor, the aryl hydrocarbon receptor (AHR). The Han/Wistar (Kuopio) (H/W) strain shows exceptional resistance to many TCDD-induced toxicities; the LD50 of >9600μg/kg for H/W rats is higher than for any other wild-type mammal known. We previously showed that this resistance primarily results from H/W rats expressing a variant AHR isoform that has a substantial portion of the AHR transactivation domain deleted. Despite this large deletion, H/W rats are not entirely refractory to the effects of TCDD; the variant AHR in these animals remains fully competent to up-regulate well-known dioxin-inducible genes. TCDD-sensitive (Long–Evans, L–E) and resistant (H/W) rats were treated with either corn-oil (with or without feed-restriction) or 100μg/kg TCDD for either four or ten days. Hepatic transcriptional profiling was done using microarrays, and was validated by RT-PCR analysis of 41 genes. A core set of genes was altered in both strains at all time points tested, including CYP1A1, CYP1A2, CYP1B1, Nqo1, Aldh3a1, Tiparp, Exoc3, and Inmt. Outside this core, the strains differed significantly in the breadth of response: three-fold more genes were altered in L–E than H/W rats. At ten days almost all expressed genes were dysregulated in L–E rats, likely reflecting emerging toxic responses. Far fewer genes were affected by feed-restriction, suggesting that only a minority of the TCDD-induced changes are secondary to the wasting syndrome. [Copyright &y& Elsevier]