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  • 1
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    Sequence and functional characterization of hypoxia inducible factors, HIF1α, HIF2αa, and HIF3α, from the estuarine fish, Fundulus heteroclitus (2017)
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    Publication Date: 2022-05-25
    Description: Author Posting. © The Author(s), 2016. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 312 (2017): R412-R425, doi:10.1152/ajpregu.00402.2016.
    Description: The hypoxia inducible factor (HIF) family of transcription factors plays central roles in the development, physiology, pathology, and environmental adaptation of animals. Because many aquatic habitats are characterized by episodes of low dissolved oxygen, fish represent ideal models to study the roles of HIF in the response to aquatic hypoxia. The estuarine fish Fundulus heteroclitus occurs in habitats prone to hypoxia, it responds to low oxygen via behavioral, physiological, and molecular changes, and one member of the HIF family, HIF2α, has been previously described. Herein, cDNA sequencing, phylogenetic analyses, and genomic approaches were used to determine other members of the HIFα family from F. heteroclitus and their relationships to HIFα subunits from other vertebrates. In vitro and cellular approaches demonstrated that full-length forms of HIF1α, 2α, and 3α independently formed complexes with the β subunit (ARNT) to bind to hypoxia response elements and activate reporter gene expression. Quantitative PCR showed that HIFα mRNA abundance varied among organs of normoxic fish in an isoform-specific fashion. Analysis of the F. heteroclitus genome revealed a locus encoding a second HIF2α, HIF2αb, a predicted protein lacking oxygen sensing and transactivation domains. Finally, sequence analyses demonstrated polymorphism in the coding sequence of each F. heteroclitus HIFα subunit, suggesting that genetic variation in these transcription factors may play a role in the variation in hypoxia responses among individuals or populations.
    Description: This research was supported in part by the National Science Foundation (IBN-0236494 and DEB-1120263) and by National Institute of Environmental Health Sciences (NIEHS) grant P42ES007381 (Superfund Basic Research Program at Boston University). Data interpretation was aided by reference to a preliminary draft of the F. heteroclitus genome sequence, which was supported by funding from the National Science Foundation (collaborative research grants DEB-1120512, DEB-1265282, DEB-1120013, DEB-1120263, DEB-1120333, DEB-1120398).
    Keywords: Environmental adaptation ; Oxygen ; Gene expression
    Repository Name: Woods Hole Open Access Server
    Type: Preprint
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  • 2
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    The molecular basis for differential dioxin sensitivity in birds : role of the aryl hydrocarbon receptor (2006)
    National Academy of Sciences
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    Publication Date: 2022-05-25
    Description: Author Posting. © National Academy of Sciences, 2006. This article is posted here by permission of National Academy of Sciences for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences 103 (2006): 6252-6257, doi:10.1073/pnas.0509950103.
    Description: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons (HAHs) are highly toxic to most vertebrate animals, but there are dramatic differences in sensitivity among species and strains. Aquatic birds including the common tern (Sterna hirundo) are highly exposed to HAHs in the environment, but are up to 250-fold less sensitive to these compounds than the typical avian model, the domestic chicken (Gallus gallus). The mechanism of HAH toxicity involves altered gene expression subsequent to activation of the aryl hydrocarbon receptor (AHR), a basic helix–loop–helix-PAS transcription factor. AHR polymorphisms underlie mouse strain differences in sensitivity to HAHs and polynuclear aromatic hydrocarbons, but the role of the AHR in species differences in HAH sensitivity is not well understood. Here, we show that although chicken and tern AHRs both exhibit specific binding of [3H]TCDD, the tern AHR has a lower binding affinity and exhibits a reduced ability to support TCDD-dependent transactivation as compared to AHRs from chicken or mouse. We further show through use of chimeric AHR proteins and site-directed mutagenesis that the difference between the chicken and tern AHRs resides in the ligand-binding domain and that two amino acids (Val-325 and Ala-381) are responsible for the reduced activity of the tern AHR. Other avian species with reduced sensitivity to HAHs also possess these residues. These studies provide a molecular understanding of species differences in sensitivity to dioxin-like compounds and suggest an approach to using the AHR as a marker of dioxin susceptibility in wildlife.
    Description: This research was supported by the National Oceanographic and Atmospheric Administration National Sea Grant College Program, Department of Commerce, under Grants NA46RG0470 and NA16RG2273.
    Keywords: Basic helix–loop–helix-PAS ; Comparative toxicology ; Mechanisms ; Risk assessment ; Susceptibility
    Repository Name: Woods Hole Open Access Server
    Type: Article
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  • 3
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    Amino acid sequence of the ligand-binding domain of the aryl hydrocarbon receptor 1 predicts sensitivity of wild birds to effects of dioxin-like compounds (2013)
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    Publication Date: 2022-05-26
    Description: Author Posting. © The Author(s), 2012. This is the author's version of the work. It is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Toxicological Sciences 131 (2013): 139-152, doi:10.1093/toxsci/kfs259.
    Description: The sensitivity of avian species to the toxic effects of dioxin-like compounds (DLCs) varies up to 1000-fold among species and this variability has been associated with inter-species differences in aryl hydrocarbon receptor 1 ligand binding domain (AHR1 LBD) sequence. We previously showed that LD50 values, based on in ovo exposures to DLCs, were significantly correlated with in vitro EC50 values obtained with a luciferase reporter gene (LRG) assay that measures AHR1-mediated induction of cytochrome P4501A in COS-7 cells transfected with avian AHR1 constructs. Those findings suggest that the AHR1 LBD sequence and the LRG assay can be used to predict avian species sensitivity to DLCs. In the present study, the AHR1 LBD sequences of 86 avian species were studied and differences at amino acid sites 256, 257, 297, 324, 337 and 380 were identified. Site-directed mutagenesis, the LRG assay and homology modeling highlighted the importance of each amino acid site in AHR1 sensitivity to 2,3,8,8-tetrachlorodibenzo-p-dioxin and other DLCs. The results of the study revealed that: (1) only amino acids at sites 324 and 380 affect the sensitivity of AHR1 expression constructs of 86 avian species to DLCs and (2) in vitro luciferase activity in AHR1 constructs containing only the LBD of the species of interest is significantly correlated (r2 = 0.93, p〈0.0001) with in ovo toxicity data for those species. These results indicate promise for the use of AHR1 LBD amino acid sequences independently, or combined with the LRG assay, to predict avian species sensitivity to DLCs.
    Description: This research was supported by unrestricted grants from the Dow Chemical Company and Georgia-Pacific LLC to the University of Ottawa, Environment Canada’s STAGE program and, in part, by a Discovery Grant from the National Science and Engineering Research Council of Canada (Project # 326415-07). The authors wish to acknowledge the support of an instrumentation grant from the Canada Foundation for Infrastructure. Professor Giesy was supported by the Canada Research Chair program and an at large Chair Professorship at the Department of Biology and Chemistry and State Key Laboratory in Marine Pollution, City University of Hong Kong, the Einstein Professor Program of the Chinese Academy of Sciences and the Visiting Professor Program of King Saud University. M. Hahn and S. Karchner were supported by NOAA Sea Grant (grant number NA06OAR4170021 (R/B-179)), and by the Walter A. and Hope Noyes Smith endowed chair.
    Description: 2013-08-24
    Keywords: Dioxin ; Risk assessment ; Bird ; Ah receptor ; Molecular toxicology
    Repository Name: Woods Hole Open Access Server
    Type: Preprint
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  • 4
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    Diversity as opportunity : insights from 600 million years of AHR evolution (2017)
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    Publication Date: 2022-05-26
    Description: © The Author(s), 2017. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Current Opinion in Toxicology 2 (2017): 58-71, doi:10.1016/j.cotox.2017.02.003
    Description: The aryl hydrocarbon receptor (AHR) was for many years of interest only to pharmacologists and toxicologists. However, this protein has fundamental roles in biology that are being revealed through studies in diverse animal species. The AHR is an ancient protein. AHR homologs exist in most major groups of modern bilaterian animals, including deuterostomes (chordates, hemichordates, echinoderms) and the two major clades of protostome invertebrates [ecdysozoans (e.g. arthropods and nematodes) and lophotrochozoans (e.g. molluscs and annelids)]. AHR homologs also have been identified in cnidarians such as the sea anemone Nematostella and in the genome of Trichoplax, a placozoan. Bilaterians, cnidarians, and placozoans form the clade Eumetazoa, whose last common ancestor lived approximately 600 million years ago (MYA). The presence of AHR homologs in modern representatives of all these groups indicates that the original eumetazoan animal possessed an AHR homolog. Studies in invertebrates and vertebrates reveal parallel functions of AHR in the development and function of sensory neural systems, suggesting that these may be ancestral roles. Vertebrate animals are characterized by the expansion and diversification of AHRs, via gene and genome duplications, from the ancestral protoAHR into at least five classes of AHR-like proteins: AHR, AHR1, AHR2, AHR3, and AHRR. The evolution of multiple AHRs in vertebrates coincided with the acquisition of high-affinity binding of halogenated and polynuclear aromatic hydrocarbons and the emergence of adaptive functions involving regulation of xenobiotic-metabolizing enzymes and roles in adaptive immunity. The existence of multiple AHRs may have facilitated subfunction partitioning and specialization of specific AHR types in some taxa. Additional research in diverse model and non-model species will continue to enrich our understanding of AHR and its pleiotropic roles in biology and toxicology.
    Description: M.E.H. and S.I.K are grateful for the long-term support of our AHR research from the National Institute of Environmental Health Sciences (NIEHS) through grants R01ES006272 and P42ES007381 (Superfund Research Program at Boston University). We also acknowledge support from a WHOI Independent Study Award funded by the Andrew W. Mellon Foundation Endowed Fund for Innovative Research. R.R.M. acknowledges support from the NIH National Center for Research Resources RI-INBRE (P20RR016457), National Science Foundation EPSCoR Cooperative Agreement #EPS-1004057, a MDIBL New Investigator Award funded by ME-INBRE (P20RR016463), and NIEHS grant P30ES003828.
    Keywords: Ah receptor ; Aryl hydrocarbon receptor ; bHLH-PAS ; Dioxin ; Evolution ; Development ; Metazoan ; Vertebrate ; Fish ; Genome duplication ; Gene expression
    Repository Name: Woods Hole Open Access Server
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