The constitutively active Ah receptor (CA-AhR) mouse as a potential model for dioxin exposure—Effects in vital organs

Brunnberg, Sara; Andersson, Patrik; Lindstam, Maria; Paulson, Ivar; Poellinger, Lorenz; Hanberg, Annika

doi:10.1016/j.tox.2006.04.045

Cited by 45 publications

(37 citation statements)

References 21 publications

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“…Pitot et al 1987; Maronpot et al 1993; Teeguarden et al 1999; Knerr and Schrenk 2006). AhR activation has been exhaustively studied by evaluating dioxin-induced CYP1A induction, tumor promotion in constitutively active AhR models and AhR polymorphism rat models that are resistant toward dioxin (Viluksela et al 1997, 2000; Pohjanvirta et al 1999; Moennikes et al 2004; Brunnberg et al 2006). Sustained AhR activation promotes two different liver tumor lineages (Walker et al 2006).…”

Section: Use Of In Vitro Systems For Predicting Liver Toxicitymentioning

confidence: 99%

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

Hewitt²,

et al. 2013

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This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-013-1078-5) contains supplementary material, which is available to authorized users.

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Section: Use Of In Vitro Systems For Predicting Liver Toxicitymentioning

confidence: 99%

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

Hewitt²,

et al. 2013

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“…To study AhR gain-of-function, transgenic mice that expressed constitutively active (CA)-AhR were bred to mimic AhR ligand exposure. These mice showed typical signs of dioxin toxicities, such as thymic involution, liver enlargement, and gastric tumors (Andersson et al, 2002;Brunnberg et al, 2006;Ito et al, 2004). These results suggest that CA-AhR is a useful tool to study the mechanism of AhR ligand toxicity.…”

Section: Introductionmentioning

confidence: 79%

Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse

et al. 2017

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-The aryl hydrocarbon receptor (AhR) avidly binds dioxin, a ubiquitous environmental contaminant. Disruption of downstream AhR signaling has been reported to alter neuronal development, and rodent offspring exposed to dioxin during gestation and lactation showed abnormalities in learning and memory, emotion, and social behavior. However, the mechanism behind the disrupted AhR signaling and developmental neurotoxicity induced by xenobiotic ligands remains elusive. Therefore, we studied how excessive AhR activation affects neuronal migration in the hippocampal CA1 region of the developing mouse brain. We transfected constitutively active (CA)-AhR, AhR, or control vector plasmids into neurons via in utero electroporation on gestational day 14 and analyzed neuronal positioning in the hippocampal CA1 region of offspring on postnatal day 14. CA-AhR transfection affected neuronal positioning, whereas no change was observed in AhR-transfected or control hippocampus. These results suggest that constitutively activated AhR signaling disrupts neuronal migration during hippocampal development. Further studies are needed to investigate whether such developmental disruption in the hippocampus leads to the abnormal cognition and behavior of rodent offspring upon maternal exposure to AhR xenobiotic ligands.

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“…Cyp1a1 and Cyp1a2 are regulated by AHR, the aryl hydrocarbon receptor, which plays an important role in cell cycle regulation, apoptosis and development (Xu et al, 2005). It is evident that some toxins such as tumorigenic polycyclic aromatic hydrocarbons (PAHs) (Martignoni et al, 2006) and carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are able to induce Cyp1a1 through AHR, and the upregulation of Cyp1a1 is considered the indicator of TCDD-induced carcinogenesis (Brunnberg et al, 2006). Thus, induction of Cyp1a1 may contribute to the toxic mechanism of Ginkgo biloba , and/or may enhance metabolic activation of the hazardous tumorigenic xenobiotics and jeopardize health.…”

Section: Discussionmentioning

confidence: 99%

Ginkgo Biloba Extract Induces Gene Expression Changes in Xenobiotics Metabolism and the Myc-Centered Network

Guo

Mei

Liao³

et al. 2010

OMICS: A Journal of Integrative Biology

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The use of herbal dietary supplements in the United States is rapidly growing and it is crucial that the quality and safety of these preparations be ensured. To date, it is still a challenge to determine the mechanisms of toxicity induced by mixtures containing many chemical components, such as herbal dietary supplements. We previously proposed that analyses of the gene expression profiles using microarrays in the livers of rodents treated with herbal dietary supplements is a potentially practical approach for understanding the mechanism of toxicity. In this study, we utilized microarrays to analyze gene expression changes in the livers of male B6C3F1 mice administered Ginkgo biloba leaf extract (GBE) by gavage for two years, and to determine pathways and mechanisms associated with GBE treatments. Analysis of 31,802 genes revealed that there were 129, 289, and 2011 genes significantly changed in the 300, 600, and 2,000 mg/kg treatment groups, respectively, when compared with control animals. Drug metabolizing genes were significantly altered in response to GBE treatments. Pathway and network analyses were applied to investigate the gene relationships, functional clustering, mechanisms involved in GBE exposure. These analyses indicate alteration in the expression of genes coding for drug metabolizing enzymes, the NRF2- mediated oxidative stress response pathway, and the Myc gene-centered network named “cell cycle, cellular movement and cancer” were found. These results indicate that Ginkgo biloba related drug metabolizing enzymes may cause herb-drug interactions and contribute to hepatotoxicity. In addition, the outcomes of pathway and network analysis may be used to elucidate the toxic mechanisms of Ginkgo biloba.

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The constitutively active Ah receptor (CA-AhR) mouse as a potential model for dioxin exposure—Effects in vital organs

Cited by 45 publications

References 21 publications

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse

Ginkgo Biloba Extract Induces Gene Expression Changes in Xenobiotics Metabolism and the Myc-Centered Network

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