Browsing by Subject "AHR"
Now showing items 1-8 of 8
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(Helsingin yliopisto, 2021)Aryylihiilivetyreseptori (AHR) ligandiin sitouduttuaan kulkeutuu solun tumaan ja aktivoi tai repressoi geenejä. Sillä on sekä ulkoisia (toksikantit ja ravinnon mukana saatavat) että sisäsyntyisiä ligandeja. Se on säilynyt evoluution kuluessa lähes kaikissa lajeissa, ja viime vuosina sen on tutkimuksissa havaittu vaikuttavan yksilön kehittymiseen. Tämä kirjallisuuskatsaus kokoaa tunnettuja vaikutuksia yksilönkehitykseen. Tutkimusta AH-reseptoriin liittyen on tehty lähinnä eläimillä. Suurin osa tutkimuksista on tehty hiirillä, mutta tutkimusta löytyy myös esimerkiksi seeprakaloista ja rotista. Iso osa katsauksen tutkimuksista on tehty AHR-poistogeenisillä hiirillä, mutta tutkimusta on tehty paljon myös AH-reseptoria aktivoivilla ympäristömyrkyillä, kuten dioksiinilla. Eniten AH-reseptori näyttäisi vaikuttavan solusykliin, kuten solujen proliferaatioon, erilaistumiseen ja solukuolemaan. AHR vaikuttaa sekä suoraan soluihin että reitteihin. Koska sekä reseptorin puute että yliaktiivisuus aiheuttavat yksilönkehitykseen ongelmia, on reseptorin oikea toiminta elimistössä välttämätöntä. AHR vaikuttaa sekä urosten että naaraiden hedelmällisyyteen. Sen on havaittu vaikuttavan seksuaalikäytökseen, sukupuolihormoneiden määrään elimistössä, sukusolujen kehitykseen ja hedelmöittymiseen sekä hedelmöityskykyyn. Maksa- ja munuaisvaikutuksia on tutkittu lähinnä poistogeenisillä eläimillä. Ongelmat ovat poistogeenisten eläinten maksan pienempi koko ja maksan ja munaisten verisuonituksen häiriöt. Veressä maksan ja munuaisten toimintaa kuvaavat veriarvot ovat poistogeenisillä eläimillä korkeammat. AH-reseptorin puute vaikuttaa myös sydän- ja verenkiertoelimistöön. AHR-poistogeenisillä hiirillä on suurempi sydän, paksumpi vasen kammio, sydämen toiminta on heikentynyt ja rasituksensietokyky huonompi kuin villityypin hiirillä. Verenkiertoelimistö ei kehity normaalisti vaan sikiöaikaisia rakenteita jää elimistöön. Myös verenpaineen säätely on heikentynyt. AH-reseptori vaikuttaa sekä veren soluihin että immuunisoluihin. AH-reseptorin puute tai sen yliaktiivisuus näyttää vaikuttavan eri solulinjoihin eri tavalla suosien tiettyjen solulinjojen proliferaatiota ja erilaistumista ja supressoiden tiettyjä solulinjoja. Hermostossa AH-reseptori tutkimusten mukaan vaikuttaa näköön, hermosoluja ympäröivien myeliinituppien kehitykseen ja suoraan kehittyviin keskushermoston osiin, erityisesti hippokampukseen ja pikkuaivoihin. Kovakudoksissa sekä AH-reseptorin yliaktiivisuus että puute aiheuttaa vakavia ongelmia kehitykseen. Liian aktiivinen AH- reseptori aiheuttaa erimerkiksi kitalakihalkion, hampaiden kehityksen hidastumisen tai pysähtymisen ja luuston epänormaalin mineralisoitumisen, kun taas reseptorin puute vaikuttaa ainakin seeprakalojen kallon kehittymiseen. Luustovaikutuksissa on sukupuolieroja niin, että naarailla AH-reseptorin epänormaalin toiminnan vaikutukset ovat suuremmat. AH-reseptorin vaikutuksissa riittää vielä paljon tutkittavaa, koska osa tutkimuksista on ristiriidassa keskenään, tarkkoja vaikutusmekanismeja ei vielä tunneta ja lajien välillä reseptorin vaikutuksessa on eroja. Tulevaisuudessa reseptorin tutkimus on tärkeää, koska tutkimusten avulla voidaan löytää muun muassa hoitokeinoja ihmisten perinnöllisiin sairauksiin.
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(Helsingin yliopisto, 2018)The arylhydrocarbon receptor (AHR) is known for its xenobiotic role. In the last decades we have realized it has an important role even in normal physiology. Earlier studies have shown different circadian behavior in mice and rats when AHR is activated with the environmental toxoid TCDD. Also, AHR knock-out (AHRKO) mice have shown to adapt quicker to new lighting conditions. The aim of this study was to chart AHRs role on the circadian behavior in rats, by comparing daily eating and drinking habits under normal lighting condition for 7 days and for 7 days after a 12-hour light shift. Tissue samples to be used in continuing studies were taken after the 14 days long follow up. These studies will chart how the circadian timekeeping genes are expressed in the central (suprachiasmatic nucleus) and periphery (liver) cells in AHRKO rats after an adaptation to phase shift compared to wild type rats. This way the study will provide information that will help us understand the role of AHR in different species regarding behavior and in continuing studies gene expression. In our study no differences in drinking and eating activity could be seen between AHRKO and wild type rats. Both groups adapted to new lighting conditions equally fast.
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(2021)The physiological functions of the aryl hydrocarbon receptor (AHR) are only beginning to unfold. Studies in wildtype and AHR knockout (AHRKO) mice have recently disclosed that AHR activity is required for obesity and steatohepatitis to develop when mice are fed with a high-fat diet (HFD). In addition, a line of AHRKO mouse has been reported to accumulate retinoids in the liver. Whether these are universal manifestations across species related to AHR activity level is not known yet. Therefore, we here subjected wildtype and AHRKO male rats (on Sprague-Dawley background) to HFD feeding coupled with free access to 10% sucrose solution and water; controls received a standard diet and water. Although the HFD-fed rats consumed more energy throughout the 24-week feeding regimen, they did not get overweight. However, relative weights of the brown and epididymal adipose tissues were elevated in HFDfed rats, while that of the liver was lower in AHRKO than wildtype rats. Moreover, the four groups exhibited diet-or genotype-dependent differences in biochemical variables, some of which suggested marked dissimilarities from AHRKO mice. Expression of pro-and anti-inflammatory genes was induced in livers of HFD-fed AHRKO rats, but histologically they did not differ from others. HFD reduced the hepatic concentrations of retinyl palmitate, 9-cis-4oxo-13,14-dihydroretinoic acid and (suggestively) retinol, whereas AHR status had no effect. Hence, the background strain/line of AHRKO rat is resistant to diet-induced obesity, and AHR does not modulate this or liver retinoid concentrations. Yet, subtle AHR-dependent differences in energy balance-related factors exist despite similar weight development. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )
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(2015)Background: 2,3,7,8-tetrachlorodibenzo-p-dixion (TCDD) is the most potent of the dioxin congeners, capable of causing a wide range of toxic effects across numerous animal models. Previous studies have demonstrated that males and females of the same species can display divergent sensitivity phenotypes to TCDD toxicities. Although it is now clear that most TCDD-induced toxic outcomes are mediated by the aryl hydrocarbon receptor (AHR), the mechanism of differential responses to TCDD exposure between sexes remains largely unknown. To investigate the differential sensitivities in male and female mice, we profiled the hepatic transcriptomic responses 4 days following exposure to various amounts of TCDD (125, 250, 500 or 1000 mu g/kg) in adult male and female C57BL/6Kuo mice. Results: Several key findings were revealed by our study. 1) Hepatic transcriptomes varied significantly between the sexes at all doses examined. 2) The liver transcriptome of males was more dysregulated by TCDD than that of females. 3) The alteration of " AHR-core" genes was consistent in magnitude, regardless of sex. 4) A subset of genes demonstrated sex-dependent TCDD-induced transcriptional changes, including Fmo3 and Nr1i3, which were significantly induced in livers of male mice only. In addition, a meta-analysis was performed to contrast transcriptomic profiles of various organisms and tissues following exposure to equitoxic doses of TCDD. Minimal overlap was observed in the differences between TCDD-sensitive or TCDD-resistant models. Conclusions: Sex-dependent sensitivities to TCDD exposure are associated with a set of sex-specific TCDD-responsive genes. In addition, complex interactions between the aryl hydrocarbon and sex hormone receptors may affect the observable differences in sensitivity phenotypes between the sexes. Further work is necessary to better understand the roles of those genes altered by TCDD in a sex-dependent manner, and their association with changes to sex hormones and receptors.
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(2015)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-rho-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 mu g/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. (C) 2014 The Authors. Published by Elsevier Ireland Ltd.
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(2015)Polychlorinated dibenzodioxins are environmental contaminants commonly produced as a by-product of industrial processes. The most potent of these, 2,3,7,8-tetrachlorodibenzo-rho-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 mu g/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 I 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 Fl1a1 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. (C) 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license.
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(2019)IMA-08401 (C2) is a novel aryl hydrocarbon receptor (AHR) agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Both compounds are converted to the AHR-active metabolite DELAQ (IMA-06201) in vivo. SAHRMs have been proposed as therapeutic options for various autoimmune disorders. Clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, their functional resemblance to the highly toxic AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) raises questions. Here, we characterize the hepatic transcriptomic changes induced by acute (single-dose) and subacute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to C2 in Sprague-Dawley rats. Exposure to C2 leads to activation of the AHR, as shown by altered transcription of Cyp1a1. We identify a heightened response early after exposure that drops off by day 10. Acute exposure to C2 leads to changes to transcription of genes involved in antiviral and antibacterial responses, which highlights the immunomodulator effects of this AHR agonist. Subacute exposure causes an oxidative stress response in the liver, the consequences of which require further study on target tissues such as the CNS and immune system, both of which may be compromised in this patient population.
