Development of yeast reporter assay for screening specific ligands of retinoic acid and retinoid X receptor subtypes

Shiizaki, Kazuhiro; Yoshikawa, Tomoya; Takada, Eiji; Hirose, Shizuma; Ito‐Harashima, Sayoko; Kawanishi, Michihiro; Yagi, Takashi

doi:10.1016/j.vascn.2014.01.007

Cited by 18 publications

(28 citation statements)

References 48 publications

(42 reference statements)

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“…We also recently showed that NP did not affect Rxrγ mRNA in mouse hippocampal neurons (Litwa et al 2014 ). Similarly, Shiizaki et al ( 2014 ) provided a list of compounds that did not alter Rxrγ gene expression (Shiizaki et al 2014 ). However, there are no relevant data from other researchers to compare with the DDE-stimulated protein levels of RXR receptors observed in the present study.…”

Section: Discussionmentioning

confidence: 99%

The Crucial Involvement of Retinoid X Receptors in DDE Neurotoxicity

et al. 2015

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Dichlorodiphenyldichloroethylene (DDE) is a primary environmental and metabolic degradation product of the pesticide dichlorodiphenyltrichloroethane (DDT). It is one of the most toxic compounds belonging to organochlorines. DDE has never been commercially produced; however, the parent pesticide DDT is still used in some developing countries for disease-vector control of malaria. DDT and DDE remain in the environment because these chemicals are resistant to degradation and bioaccumulate in the food chain. Little is known, however, about DDE toxicity during the early stages of neural development. The results of the present study demonstrate that DDE induced a caspase-3-dependent apoptosis and caused the global DNA hypomethylation in mouse embryonic neuronal cells. This study also provided evidence for DDE-isomer-non-specific alterations of retinoid X receptor α (RXRα)- and retinoid X receptor β (RXRβ)-mediated intracellular signaling, including changes in the levels of the receptor mRNAs and changes in the protein levels of the receptors. DDE-induced stimulation of RXRα and RXRβ was verified using selective antagonist and specific siRNAs. Co-localization of RXRα and RXRβ was demonstrated using confocal microscopy. The apoptotic action of DDE was supported at the cellular level through Hoechst 33342 and calcein AM staining experiments. In conclusion, the results of the present study demonstrated that the stimulation of RXRα- and RXRβ-mediated intracellular signaling plays an important role in the propagation of DDE-induced apoptosis during early stages of neural development.

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Section: Discussionmentioning

confidence: 99%

The Crucial Involvement of Retinoid X Receptors in DDE Neurotoxicity

et al. 2015

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“…In this case, effort would be directed toward making the causal linkages-via additional experiments, literature reviews, etc.-between the AO and the KEs that precede it (e.g., Ankley et al, 2009;Kimber et al, 2014). Alternatively, an MIE (e.g., a receptor-ligand interaction) may be well characterized with QSAR models and/or in vitro assays that allow chemicals to be rapidly screened for their affinity to the receptor (e.g., Farmahin et al, 2012;Shiizaki et al, 2014;Zhang et al, 2013). However, the understanding of the toxicological significance of those receptor interactions needs to be established.…”

Section: Aop Development Strategiesmentioning

confidence: 99%

Adverse Outcome Pathway (AOP) Development I: Strategies and Principles

et al. 2014

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An adverse outcome pathway (AOP) is a conceptual framework that organizes existing knowledge concerning biologically plausible, and empirically supported, links between molecular-level perturbation of a biological system and an adverse outcome at a level of biological organization of regulatory relevance. Systematic organization of information into AOP frameworks has potential to improve regulatory decision-making through greater integration and more meaningful use of mechanistic data. However, for the scientific community to collectively develop a useful AOP knowledgebase that encompasses toxicological contexts of concern to human health and ecological risk assessment, it is critical that AOPs be developed in accordance with a consistent set of core principles. Based on the experiences and scientific discourse among a group of AOP practitioners, we propose a set of five fundamental principles that guide AOP development: (1) AOPs are not chemical specific; (2) AOPs are modular and composed of reusable components-notably key events (KEs) and key event relationships (KERs); (3) an individual AOP, composed of a single sequence of KEs and KERs, is a pragmatic unit of AOP development and evaluation; (4) networks composed of multiple AOPs that share common KEs and KERs are likely to be the functional unit of prediction for most real-world scenarios; and (5) AOPs are living documents that will evolve over time as new knowledge is generated. The goal of the present article was to introduce some strategies for AOP development and detail the rationale behind these 5 key principles. Consideration of these principles addresses many of the current uncertainties regarding the AOP framework and its application and is intended to foster greater consistency in AOP development.

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“…Moreover, TBT is not only a PPARγ agonist, but also is an agonist for retinoid X receptors (RXR) α and β (le Maire et al 2009; Shiizaki et al 2014). The dual ligand nature of the organotins raises the possibility that RXR could contribute to TBT-induced effects on MSC differentiation, independently of PPARγ.…”

Section: Introductionmentioning

confidence: 99%

Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models

Kim

Monti

et al. 2018

Arch Toxicol

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Tributyltin (TBT), a peroxisome proliferator-activated receptor γ (PPARγ)/retinoid X receptor (RXR) ligand and founding member of the environmental obesogen chemical class, induces adipocyte differentiation and suppresses bone formation. A growing number of environmental PPARγ ligands are being identified. However, the potential for environmental PPARγ ligands to induce adverse metabolic effects has been questioned because PPARγ is a therapeutic target in treatment of type II diabetes. We evaluated the molecular consequences of TBT exposure during bone marrow multipotent mesenchymal stromal cell (BM-MSC) differentiation in comparison to rosiglitazone, a therapeutic PPARγ ligand, and LG100268, a synthetic RXR ligand. Mouse primary BM-MSCs (female, C57BL/6J) undergoing bone differentiation were exposed to maximally efficacious and human relevant concentrations of rosiglitazone (100 nM), LG100268 (100 nM) or TBT (80 nM) for 4 days. Gene expression was assessed using microarrays, and in silico functional annotation was performed using pathway enrichment analysis approaches. Pathways related to osteogenesis were downregulated by all three ligands, while pathways related to adipogenesis were upregulated by rosiglitazone and TBT. However, pathways related to mitochondrial biogenesis and brown-in-white (brite) adipocyte differentiation were more significantly upregulated in rosiglitazone-treated than TBT-treated cells. The lack of induction of genes involved in adipocyte energy dissipation by TBT was confirmed by an independent gene expression analysis in BM-MSCs undergoing adipocyte differentiation and by analysis of a publically available 3T3 L1 data set. Furthermore, rosiglitazone, but not TBT, induced mitochondrial biogenesis and respiration. This study is the first to show that an environmental PPARγ ligand has a limited capacity to induce health-promoting activities of PPARγ.

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Development of yeast reporter assay for screening specific ligands of retinoic acid and retinoid X receptor subtypes

Abstract: The present assay yeasts may be valuable tools for subtype-specific assessments of unidentified environmental ligand chemicals and receptor-specific pharmaceuticals.

Cited by 18 publications

References 48 publications

The Crucial Involvement of Retinoid X Receptors in DDE Neurotoxicity

The Crucial Involvement of Retinoid X Receptors in DDE Neurotoxicity

Adverse Outcome Pathway (AOP) Development I: Strategies and Principles

Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models

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