Genetic and pharmacological analysis identifies a physiological role for the AHR in epidermal differentiation

PubMed Central

van den Bogaard, Ellen; Podolsky, Michael; Smits, Jos; Cui, Xiao; John, Christian; Gowda, Krishne; Desai, Dhimant; Amin, Shantu; Schalkwijk, Joost; Perdew, Gary H.

2015-01-01

Stimulation of the aryl hydrocarbon receptor (AHR) by xenobiotics is known to affect epidermal differentiation and skin barrier formation. The physiological role of endogenous AHR signaling in keratinocyte differentiation is not known. We used murine and human skin models to address the hypothesis that AHR activation is required for normal keratinocyte differentiation. Using transcriptome analysis of Ahr-/- and Ahr+/+ murine keratinocytes, we found significant enrichment of differentially expressed genes linked to epidermal differentiation. Primary Ahr-/- keratinocytes showed a significant reduction in terminal differentiation gene and protein expression, similar to Ahr+/+ keratinocytes treated with AHR antagonists GNF351 and CH223191, or the selective AHR modulator (SAhRM), SGA360. In vitro keratinocyte differentiation led to increased AHR levels and subsequent nuclear translocation, followed by induced CYP1A1 gene expression. Monolayer cultured primary human keratinocytes treated with AHR antagonists also showed an impaired terminal differentiation program. Inactivation of AHR activity during human skin equivalent development severely impaired epidermal stratification, terminal differentiation protein expression and stratum corneum formation. As disturbed epidermal differentiation is a main feature of many skin diseases, pharmacological agents targeting AHR signaling or future identification of endogenous keratinocyte-derived AHR ligands should be considered as potential new drugs in dermatology. PMID:25602157

Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands.

PubMed

Procházková, Jiřina; Strapáčová, Simona; Svržková, Lucie; Andrysík, Zdeněk; Hýžďalová, Martina; Hrubá, Eva; Pěnčíková, Kateřina; Líbalová, Helena; Topinka, Jan; Kléma, Jiří; Espinosa, Joaquín M; Vondráček, Jan; Machala, Miroslav

2018-08-01

Exposure to persistent ligands of aryl hydrocarbon receptor (AhR) has been found to cause lung cancer in experimental animals, and lung adenocarcinomas are often associated with enhanced AhR expression and aberrant AhR activation. In order to better understand the action of toxic AhR ligands in lung epithelial cells, we performed global gene expression profiling and analyze TCDD-induced changes in A549 transcriptome, both sensitive and non-sensitive to CH223191 co-treatment. Comparison of our data with results from previously reported microarray and ChIP-seq experiments enabled us to identify candidate genes, which expression status reflects exposure of lung cancer cells to TCDD, and to predict processes, pathways (e.g. ER stress, Wnt/β-cat, IFNɣ, EGFR/Erbb1), putative TFs (e.g. STAT, AP1, E2F1, TCF4), which may be implicated in adaptive response of lung cells to TCDD-induced AhR activation. Importantly, TCDD-like expression fingerprint of selected genes was observed also in A549 cells exposed acutely to both toxic (benzo[a]pyrene, benzo[k]fluoranthene) and endogenous AhR ligands (2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester and 6-formylindolo[3,2-b]carbazole). Overall, our results suggest novel cellular candidates, which could help to improve monitoring of AhR-dependent transcriptional activity during acute exposure of lung cells to distinct types of environmental pollutants. Copyright © 2018 Elsevier B.V. All rights reserved.

Constitutive expression of the AHR signaling pathway in a bovine mammary epithelial cell line and modulation by dioxin-like PCB and other AHR ligands.

PubMed

Girolami, Flavia; Spalenza, Veronica; Manzini, Livio; Carletti, Monica; Nebbia, Carlo

2015-01-05

Environmental pollutants, such as dioxin-like (DL) PCBs, benzo(a) pyrene (B[a]P), and flavonoids are aryl hydrocarbon receptor (AHR) ligands and may be excreted in dairy milk. The expression of AHR-target genes, particularly those involved in xenobiotic biotransformation, and their modulation by two DL-PCBs, B[a]P, and β-naphthoflavone was investigated in a bovine mammary epithelial cell line (BME-UV). As assessed by quantitative PCR, BME-UV cells expressed a functional AHR signaling pathway. All the AHR ligands induced a concentration-related increase in the transcription of cytochrome P450 1A1 and 1B1, known to be implicated in the bioactivation of several xenobiotics. Conversely, genes encoding for antioxidant and detoxifying enzymes, like quinone oxidoreductase or glutathione S-transferase A2, were not affected or even depressed. This study demonstrates the occurrence and the modulation by different AHR-ligands of genes involved in xenobiotic metabolism in BME-UV cells, with the potential generation of (re) active metabolites that may damage mammary tissue and/or affect animal or human health via the contaminated milk. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Bidirectional communication between the Aryl hydrocarbon Receptor (AhR) and the microbiome tunes host metabolism.

PubMed

Korecka, Agata; Dona, Anthony; Lahiri, Shawon; Tett, Adrian James; Al-Asmakh, Maha; Braniste, Viorica; D'Arienzo, Rossana; Abbaspour, Afrouz; Reichardt, Nicole; Fujii-Kuriyama, Yoshiaki; Rafter, Joseph; Narbad, Arjan; Holmes, Elaine; Nicholson, Jeremy; Arulampalam, Velmurugesan; Pettersson, Sven

2016-01-01

The ligand-induced transcription factor, aryl hydrocarbon receptor (AhR) is known for its capacity to tune adaptive immunity and xenobiotic metabolism-biological properties subject to regulation by the indigenous microbiome. The objective of this study was to probe the postulated microbiome-AhR crosstalk and whether such an axis could influence metabolic homeostasis of the host. Utilising a systems-biology approach combining in-depth 1 H-NMR-based metabonomics (plasma, liver and skeletal muscle) with microbiome profiling (small intestine, colon and faeces) of AhR knockout (AhR -/- ) and wild-type (AhR +/+ ) mice, we assessed AhR function in host metabolism. Microbiome metabolites such as short-chain fatty acids were found to regulate AhR and its target genes in liver and intestine. The AhR signalling pathway, in turn, was able to influence microbiome composition in the small intestine as evident from microbiota profiling of the AhR +/+ and AhR -/- mice fed with diet enriched with a specific AhR ligand or diet depleted of any known AhR ligands. The AhR -/- mice also displayed increased levels of corticosterol and alanine in serum. In addition, activation of gluconeogenic genes in the AhR -/- mice was indicative of on-going metabolic stress. Reduced levels of ketone bodies and reduced expression of genes involved in fatty acid metabolism in the liver further underscored this observation. Interestingly, exposing AhR -/- mice to a high-fat diet showed resilience to glucose intolerance. Our data suggest the existence of a bidirectional AhR-microbiome axis, which influences host metabolic pathways.

SLC6A19 is a novel putative gene, induced by dioxins via AhR in human hepatoma HepG2 cells.

PubMed

Tian, Wenjing; Fu, Hualing; Xu, Tuan; Xu, Sherry Li; Guo, Zhiling; Tian, Jijing; Tao, Wuqun; Xie, Heidi Qunhui; Zhao, Bin

2018-06-01

The aryl hydrocarbon receptor (AhR) plays an important role in mediating dioxins toxicity. Currently, genes of P450 families are major research interests in studies on AhR-mediated gene alterations caused by dioxins. Genes related to other metabolic pathways or processes may be also responsive to dioxin exposures. Amino acid transporter B0AT1 (encoded by SLC6A19) plays a decisive role in neutral amino acid transport which is present in kidney, intestine and liver. However, effects of dioxins on its expression are still unknown. In the present study, we focused on the effects of dioxin and dioxin-like compounds on SLC6A19 expression in HepG2 cells. We identified SLC6A19 as a novel putative target gene of AhR activation in HepG2 cells. 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) increased the expression of SLC6A19 in time- and concentration-dependent manners. Using AhR antagonist CH223191 and/or siRNA assays, we demonstrated that certain AhR agonists upregulated SLC6A19 expression via AhR, including TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (1,2,3,7,8-PeCDD), 2,3,4,7,8- pentachlorodibenzofuran (2,3,4,7,8-PeCDF) and PCB126. In addition, the expression of B0AT1 was also significantly induced by TCDD in HepG2 cells. Our study suggested that dioxins might affect the transcription and translation of SLC6A19 in HepG2 cells, which might be a novel putative gene to assess dioxins' toxicity in amino acid transport and metabolism in liver. Copyright © 2018 Elsevier Ltd. All rights reserved.

Overexpression of aryl hydrocarbon receptor (AHR) signalling pathway in human meningioma.

PubMed

Talari, Noble Kumar; Panigrahi, Manas K; Madigubba, Sailaja; Phanithi, Prakash Babu

2018-04-01

Aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor and involved in tumorigenesis of many cancers. However there are no reports on AHR in human meningioma. Therefore we examined the status of the AHR and its signalling molecules in human meningioma by using tumor biopsy samples and autopsy control meninges. We report the up regulation of AHR pathway genes like aryl hydrocarbon receptor nuclear translocator (ARNT), aldehyde dehydrogenase1family memberA3 (ALDH1A3), cytochrome P450, family1, subfamily A polypeptide1 (CYP1A1) and TCCD induced poly ADP ribose polymerase (TIPARP) gene expression in human meningioma. Further, AHR protein expression was found to be up regulated in all grades of human meningioma. We found that AHR localized in the nucleus for high grade anaplastic meningioma through immunohistochemical analysis. Since AHR signalling pathway was known to involve in inhibition of apoptosis in cancer cells, we evaluated the cyclophilin D levels which maintains mitochondrial permeability transition pore a critical event during apoptosis. We report that cyclophilin D levels were upregulated in all grades of human meningioma compared to control meninges. Finally we also evaluated c-Fos protein levels as its levels were regulated by AHR. Here we report that c-Fos protein levels were down regulated in all grades of human meningioma compared to control meninges. To sum-up we found that AHR signalling pathway components were upregulated, as the grade of the meningioma progresses from low to high grade, suggesting an important role of AHR signalling pathway in human meningioma.

4-Nitrophenol exposure alters the AhR signaling pathway and related gene expression in the rat liver.

PubMed

Li, Ruonan; Song, Meiyan; Li, Zhi; Li, Yansen; Watanabe, Gen; Nagaoka, Kentaro; Taya, Kazuyoshi; Li, Chunmei

2017-02-01

4-Nitrophenol (PNP) is well known as an environmental endocrine disruptor. The aim of this study was to clarify the mechanism of PNP-induced liver damage and determine the regulatory involvement of the aryl hydrocarbon receptor (AhR) signaling pathway and associated gene expression. Immature male Wistar-Imamichi rats (28 days old) were randomly divided into control and PNP groups, which consisted of 1- and 3-day exposure (1 DE and 3 DE, respectively) and 3-day exposure followed by 3-day recovery (3 DE + 3 DR), groups. Each group was administered the vehicle or PNP (200 mg kg -1 body weight). The body and liver weight were significantly decreased in the 3 DE group. The mRNA expression levels of estrogen receptor-α (ERα), glutathione S-transferase (GST) and AhR exhibited a significant increase in the 1 DE group whereas, in contrast, that of cytochrome P450 (CYP) 1A1 decreased significantly in the 3 DE +3 DR group. AhR and CYP1A1 proteins were detected in the cytoplasm of hepatocytes of the 1 DE and 3 DE +3 DR groups whereas the ERα protein was found in the hepatocyte nuclei of the 1 DE and 3 DE groups. The present study demonstrates that PNP activated the AhR signaling pathway and regulated related CYP1A1 and GST gene expression in the liver. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Aryl hydrocarbon receptor (AHR) in the cnidarian Nematostella vectensis: comparative expression, protein interactions, and ligand binding.

PubMed

Reitzel, Adam M; Passamaneck, Yale J; Karchner, Sibel I; Franks, Diana G; Martindale, Mark Q; Tarrant, Ann M; Hahn, Mark E

2014-02-01

The aryl hydrocarbon receptor (AHR) is a member of the basic helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) family of transcription factors and has diverse roles in development, physiology, and environmental sensing in bilaterian animals. Studying the expression of conserved genes and function of proteins in outgroups to protostomes and deuterostomes assists in understanding the antiquity of gene function and deciphering lineage-specific differences in these bilaterian clades. We describe the developmental expression of AHR from the sea anemone Nematostella vectensis and compare its expression with three other members of the bHLH-PAS family (AHR nuclear translocator (ARNT), Cycle, and a proto-Single-Minded/Trachealess). NvAHR expression was highest early in the larval stage with spatial expression in the basal portion of the ectoderm that became increasingly restricted to the oral pole with concentrated expression in tentacles of the juvenile polyp. The other bHLH-PAS genes showed a divergent expression pattern in later larval stages and polyps, in which gene expression was concentrated in the aboral end, with broader expression in the endoderm later in development. In co-immunoprecipitation assays, we found no evidence for heterodimerization of AHR with ARNT, contrary to the conservation of this specific interaction in all bilaterians studied to date. Similar to results with other invertebrate AHRs but in contrast to vertebrate AHRs, NvAHR failed to bind two prototypical xenobiotic AHR ligands (2,3,7,8-tetrachlorodibenzo-p-dioxin, β-naphthoflavone). Together, our data suggest that AHR's original function in Eumetazoa likely involved developmental patterning, potentially of neural tissue. The role of heterodimerization in the function of AHR may have arisen after the cnidarian-bilaterian ancestor. The absence of xenobiotic binding to NvAHR further supports a hypothesis for a derived role of this protein in chemical sensing within the chordates.

Aryl hydrocarbon receptor (AHR) in the cnidarian Nematostella vectensis: comparative expression, protein interactions, and ligand binding

PubMed Central

Reitzel, Adam M.; Passamaneck, Yale J.; Karchner, Sibel I.; Franks, Diana G.; Martindale, Mark Q.; Tarrant, Ann M.; Hahn, Mark E.

2014-01-01

The aryl hydrocarbon receptor (AHR) is a member of the basic-helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) family of transcription factors and has diverse roles in development, physiology, and environmental sensing in bilaterian animals. Studying the expression of conserved genes and function of proteins in outgroups to protostomes and deuterostomes assists in understanding the antiquity of gene function and deciphering lineage-specific differences in these bilaterian clades. We describe the developmental expression of AHR from the sea anemone Nematostella vectensis and compare its expression with three other members of the bHLH-PAS family (AHR nuclear translocator (ARNT), Cycle, and a proto-Single-Minded/Trachaeless). NvAHR expression was highest early in the larval stage with spatial expression in the basal portion of the ectoderm that became increasingly restricted to the oral pole with concentrated expression in tentacles of the juvenile polyp. The other bHLH-PAS genes showed a divergent expression pattern in later larval stages and polyps, in which gene expression was concentrated in the aboral end, with broader expression in the endoderm later in development. In co-immunoprecipitation assays, we found no evidence for heterodimerization of AHR with ARNT, contrary to the conservation of this specific interaction in all bilaterians studied to date. Similar to results with other invertebrate AHRs but in contrast to vertebrate AHRs, NvAHR failed to bind two prototypical xenobiotic AHR ligands (TCDD, BNF). Together, our data suggest that AHR's original function in Eumetazoa likely involved developmental patterning, potentially of neural tissue. The role of heterodimerization in the function of AHR may have arisen after the cnidarian-bilaterian ancestor. The absence of xenobiotic binding to NvAHR further supports a hypothesis for a derived role of this protein in chemical sensing within the chordates. PMID:24292160

Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wincent, Emma; Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm; Stegeman, John J.

2015-04-15

Wnt/β-catenin signaling regulates essential biological functions and acts in developmental toxicity of some chemicals. The aryl hydrocarbon receptor (AHR) is well-known to mediate developmental toxicity of persistent dioxin-like compounds (DLCs). Recent studies indicate a crosstalk between β-catenin and the AHR in some tissues. However the nature of this crosstalk in embryos is poorly known. We observed that zebrafish embryos exposed to the β-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). This led us to investigate the AHR interaction with β-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of β-catenin signaling. We examinedmore » phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a β-catenin activator, 1-azakenpaullone, alone or with AHR agonists, either PCB126 or 6-formylindolo[3,2-b]carbazole (FICZ). Alone 1-azakenpaullone and XAV939 both were embryo-toxic, and we found that in the presence of FICZ, the toxicity of 1-azakenpaullone decreased while the toxicity of XAV939 increased. This rescue of 1-azakenpaullone effects occurred in the time window of Ahr2-mediated toxicity and was reversed by morpholino-oligonucleotide knockdown of Ahr2. Regarding PCB126, addition of either 1-azakenpaullone or XAV939 led to lower mortality than with PCB126 alone but surviving embryos showed severe edemas. 1-Azakenpaullone induced transcription of β-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of β-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating β-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes.« less

Diversity as Opportunity: Insights from 600 Million Years of AHR Evolution.

PubMed

Hahn, Mark E; Karchner, Sibel I; Merson, Rebeka R

2017-02-01

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.

Diversity as Opportunity: Insights from 600 Million Years of AHR Evolution

PubMed Central

Hahn, Mark E.; Karchner, Sibel I.; Merson, Rebeka R.

2017-01-01

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. PMID:28286876

Aryl hydrocarbon receptor (AHR) is a potential tumour suppressor in pituitary adenomas.

PubMed

Formosa, R; Borg, J; Vassallo, J

2017-08-01

Pituitary adenomas (PA) represent the largest group of intracranial neoplasms and yet the molecular mechanisms driving this disease remain largely unknown. The aim of this study was to use a high-throughput screening method to identify molecular pathways that may be playing a significant and consistent role in PA. RNA profiling using microarrays on eight local PAs identified the aryl hydrocarbon receptor (AHR) signalling pathway as a key canonical pathway downregulated in all PA types. This was confirmed by real-time PCR in 31 tumours. The AHR has been shown to regulate cell cycle progression in various cell types; however, its role in pituitary tissue has never been investigated. In order to validate the role of AHR in PA behaviour, further functional studies were undertaken. Over-expression of AHR in GH3 cells revealed a tumour suppressor potential independent of exogenous ligand activation by benzo α-pyrene (BαP). Cell cycle analysis and quantitative PCR of cell cycle regulator genes revealed that both unstimulated and BαP-stimulated AHR reduced E2F-driven transcription and altered expression of cell cycle regulator genes, thus increasing the percentage of cells in G 0 /G 1 phase and slowing the proliferation rate of GH3 cells. Co-immunoprecipitation confirmed the interaction between AHR and retinoblastoma (Rb1) protein supporting this as a functional mechanism for the observed reduction. Endogenous Ahr reduction using silencing RNA confirmed the tumour suppressive function of the Ahr. These data support a mechanistic pathway for the putative tumour suppressive role of AHR specifically in PA, possibly through its role as a cell cycle co-regulator, even in the absence of exogenous ligands. © 2017 The authors.

Aryl hydrocarbon receptor (AHR) is a potential tumour suppressor in pituitary adenomas

PubMed Central

Formosa, R; Borg, J

2017-01-01

Pituitary adenomas (PA) represent the largest group of intracranial neoplasms and yet the molecular mechanisms driving this disease remain largely unknown. The aim of this study was to use a high-throughput screening method to identify molecular pathways that may be playing a significant and consistent role in PA. RNA profiling using microarrays on eight local PAs identified the aryl hydrocarbon receptor (AHR) signalling pathway as a key canonical pathway downregulated in all PA types. This was confirmed by real-time PCR in 31 tumours. The AHR has been shown to regulate cell cycle progression in various cell types; however, its role in pituitary tissue has never been investigated. In order to validate the role of AHR in PA behaviour, further functional studies were undertaken. Over-expression of AHR in GH3 cells revealed a tumour suppressor potential independent of exogenous ligand activation by benzo α-pyrene (BαP). Cell cycle analysis and quantitative PCR of cell cycle regulator genes revealed that both unstimulated and BαP-stimulated AHR reduced E2F-driven transcription and altered expression of cell cycle regulator genes, thus increasing the percentage of cells in G0/G1 phase and slowing the proliferation rate of GH3 cells. Co-immunoprecipitation confirmed the interaction between AHR and retinoblastoma (Rb1) protein supporting this as a functional mechanism for the observed reduction. Endogenous Ahr reduction using silencing RNA confirmed the tumour suppressive function of the Ahr. These data support a mechanistic pathway for the putative tumour suppressive role of AHR specifically in PA, possibly through its role as a cell cycle co-regulator, even in the absence of exogenous ligands. PMID:28649092

AIP mutations impair AhR signaling in pituitary adenoma patients fibroblasts and in GH3 cells.

PubMed

Lecoq, Anne-Lise; Viengchareun, Say; Hage, Mirella; Bouligand, Jérôme; Young, Jacques; Boutron, Audrey; Zizzari, Philippe; Lombès, Marc; Chanson, Philippe; Kamenický, Peter

2016-05-01

Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose humans to pituitary adenomas through unknown molecular mechanisms. The best-known interacting partner of AIP is the aryl hydrocarbon receptor (AhR), a transcription factor that mediates the effects of xenobiotics implicated in carcinogenesis. As 75% of AIP mutations disrupt the physical and/or functional interaction with AhR, we postulated that the tumorigenic potential of AIP mutations might result from altered AhR signaling. We evaluated the impact of AIP mutations on the AhR signaling pathway, first in fibroblasts from AIP-mutated patients with pituitary adenomas, by comparison with fibroblasts from healthy subjects, then in transfected pituitary GH3 cells. The AIP protein level in mutated fibroblasts was about half of that in cells from healthy subjects, but AhR expression was unaffected. Gene expression analyses showed significant modifications in the expression of the AhR target genes CYP1B1 and AHRR in AIP-mutated fibroblasts, both before and after stimulation with the endogenous AhR ligand kynurenine. Kynurenine increased Cyp1b1 expression to a greater extent in GH3 cells overexpressing wild type compared with cells expressing mutant AIP Knockdown of endogenous Aip in these cells attenuated Cyp1b1 induction by the AhR ligand. Both mutant AIP expression and knockdown of endogenous Aip affected the kynurenine-dependent GH secretion of GH3 cells. This study of human fibroblasts bearing endogenous heterozygous AIP mutations and transfected pituitary GH3 cells shows that AIP mutations affect the AIP protein level and alter AhR transcriptional activity in a gene- and tissue-dependent manner. © 2016 Society for Endocrinology.

Pityriazepin and other potent AhR ligands isolated from Malassezia furfur yeast

PubMed Central

Mexia, Nikitia; Gaitanis, George; Velegraki, Aristea; Soshilov, Anatoly; Denison, Michael S.; Magiatis, Prokopios

2015-01-01

Malassezia furfur yeast strains isolated from diseased human skin preferentially biosynthesize indole alkaloids which can be detected in human skin and are highly potent activators of the aryl hydrocarbon receptor (AhR) and AhR-dependent gene expression. Chemical analysis of an EtOAc extract of a M. furfur strain obtained from diseased human skin and grown on L-tryptophan agar revealed several known AhR active tryptophan metabolites along with a previously unidentified compound, pityriazepin. While its structure resembled that of the known alkaloid pityriacitrin, the comprised pyridine ring had been transformed into an azepinone. The indoloazepinone scaffold of pityriazepin is extremely rare in nature and has only been reported once previously. Pityriazepin, like the other isolated compounds, was found to be a potent activator of the AhR-dependent reporter gene assays in recombinant cell lines derived from four different species, although significant species differences in relative potency was observed. The ability of pityriazepin to competitively bind to the AhR and directly stimulate AhR DNA binding classified it as a new naturally-occurring potent AhR agonist. Malassezia furfur produces an expanded collection of extremely potent naturally occurring AhR agonists, which produce their biological effects in a species-specific manner.1 PMID:25721496

Bidirectional communication between the Aryl hydrocarbon Receptor (AhR) and the microbiome tunes host metabolism

PubMed Central

Korecka, Agata; Dona, Anthony; Lahiri, Shawon; Tett, Adrian James; Al-Asmakh, Maha; Braniste, Viorica; D’Arienzo, Rossana; Abbaspour, Afrouz; Reichardt, Nicole; Fujii-Kuriyama, Yoshiaki; Rafter, Joseph; Narbad, Arjan; Holmes, Elaine; Nicholson, Jeremy; Arulampalam, Velmurugesan; Pettersson, Sven

2016-01-01

The ligand-induced transcription factor, aryl hydrocarbon receptor (AhR) is known for its capacity to tune adaptive immunity and xenobiotic metabolism—biological properties subject to regulation by the indigenous microbiome. The objective of this study was to probe the postulated microbiome-AhR crosstalk and whether such an axis could influence metabolic homeostasis of the host. Utilising a systems-biology approach combining in-depth 1H-NMR-based metabonomics (plasma, liver and skeletal muscle) with microbiome profiling (small intestine, colon and faeces) of AhR knockout (AhR−/−) and wild-type (AhR+/+) mice, we assessed AhR function in host metabolism. Microbiome metabolites such as short-chain fatty acids were found to regulate AhR and its target genes in liver and intestine. The AhR signalling pathway, in turn, was able to influence microbiome composition in the small intestine as evident from microbiota profiling of the AhR+/+ and AhR−/− mice fed with diet enriched with a specific AhR ligand or diet depleted of any known AhR ligands. The AhR−/− mice also displayed increased levels of corticosterol and alanine in serum. In addition, activation of gluconeogenic genes in the AhR−/− mice was indicative of on-going metabolic stress. Reduced levels of ketone bodies and reduced expression of genes involved in fatty acid metabolism in the liver further underscored this observation. Interestingly, exposing AhR−/− mice to a high-fat diet showed resilience to glucose intolerance. Our data suggest the existence of a bidirectional AhR-microbiome axis, which influences host metabolic pathways. PMID:28721249

The role of aryl hydrocarbon receptor (AhR) in the pathology of pleomorphic adenoma in parotid gland.

PubMed

Drozdzik, Agnieszka; Kowalczyk, Robert; Lipski, Mariusz; Łapczuk, Joanna; Urasinska, Elzbieta; Kurzawski, Mateusz

2016-01-01

Pleomorphic adenoma (benign mixed tumor) is one of the most common salivary gland tumors. However, molecular mechanisms implicated in its development are not entirely defined. Therefore, the study aimed at definition of aryl hydrocarbon receptor (AhR) involvement in pleomorphic adenoma pathology, as the AhR controlled gene system was documented to play a role in development of various human tumors. The study was carried out in pleomorphic adenoma and control parotid gland tissues where gene expression of AHR, AhR nuclear translocator (ARNT), AhR repressor (AHRR), as well as AhR controlled genes: CYP1A1 and CYP1B1, at mRNA and protein (immunohistochemistry) levels were studied. Functional evaluation of AhR system was evaluated in HSY cells (human parotid gland adenocarcinoma cells) using 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as AhR specific inducer. Pleomorphic adenoma specimens showed cytoplasmic and nuclear AhR expression in epithelial cells as well as in mesenchymal cells. In parotid gland AhR was expressed in cytoplasm of duct cells. Quantitative expression at mRNA level showed significantly higher expression of AHR, ARNT and CYP1B1, and comparable levels of CYP1A1 in pleomorphic adenoma tissue in comparison to healthy parotid gland. The HSY cell study revealed significantly higher expression level of AHRR in HSY as compared with MCF-7 cells (human breast adenocarcinoma cell line used as reference). Upon TCDD stimulation a drop in AHRR level in HSY cells and an increase in MCF-7 cells were observed. The HSY and MCF-7 cell proliferation rate (measured by WST-1 test) was not affected by TCDD. Summarizing both in vitro and in vivo observations it can be stated that AhR system may play a role in the pathology of pleomorphic adenoma. Copyright © 2015. Published by Elsevier Ltd.

Genome-wide mapping and analysis of aryl hydrocarbon receptor (AHR)- and aryl hydrocarbon receptor repressor (AHRR)-binding sites in human breast cancer cells.

PubMed

Yang, Sunny Y; Ahmed, Shaimaa; Satheesh, Somisetty V; Matthews, Jason

2018-01-01

The aryl hydrocarbon receptor (AHR) mediates the toxic actions of environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD), and also plays roles in vascular development, the immune response, and cell cycle regulation. The AHR repressor (AHRR) is an AHR-regulated gene and a negative regulator of AHR; however, the mechanisms of AHRR-dependent repression of AHR are unclear. In this study, we compared the genome-wide binding profiles of AHR and AHRR in MCF-7 human breast cancer cells treated for 24 h with TCDD using chromatin immunoprecipitation followed by next-generation sequencing (ChIP-Seq). We identified 3915 AHR- and 2811 AHRR-bound regions, of which 974 (35%) were common to both datasets. When these 24-h datasets were also compared with AHR-bound regions identified after 45 min of TCDD treatment, 67% (1884) of AHRR-bound regions overlapped with those of AHR. This analysis identified 994 unique AHRR-bound regions. AHRR-bound regions mapped closer to promoter regions when compared with AHR-bound regions. The AHRE was identified and overrepresented in AHR:AHRR-co-bound regions, AHR-only regions, and AHRR-only regions. Candidate unique AHR- and AHRR-bound regions were validated by ChIP-qPCR and their ability to regulate gene expression was confirmed by luciferase reporter gene assays. Overall, this study reveals that AHR and AHRR exhibit similar but also distinct genome-wide binding profiles, supporting the notion that AHRR is a context- and gene-specific repressor of AHR activity.

Suppression of CYP1 members of the AHR response by pathogen-associated molecular patterns.

PubMed

Peres, Adam G; Zamboni, Robert; King, Irah L; Madrenas, Joaquín

2017-12-01

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that triggers a broad response, which includes the regulation of proinflammatory cytokine production by monocytes and macrophages. AHR is negatively regulated by a set of genes that it transcriptionally activates, including the AHR repressor ( Ahrr ) and the cytochrome P450 1 ( Cyp1 ) family, which are critical for preventing exacerbated AHR activity. An imbalance in these regulatory mechanisms has been shown to cause severe defects in lymphoid cells. Therefore, we wanted to assess how AHR activation is regulated in monocytes and macrophages in the context of innate immune responses induced by pathogen-associated molecular patterns (PAMPs). We found that concomitant stimulation of primary human monocytes with PAMPs and the AHR agonist 6-formylindolo(3,2-b)carbazole (FICZ) led to a selective dose-dependent inhibition of Cyp1 family members induction. Two other AHR-dependent genes [ Ahrr and NADPH quinone dehydrogenase 1 ( Nqo1 )] were not affected under these conditions, suggesting a split in the AHR regulation by PAMPs. This down-regulation of Cyp1 family members did not require de novo protein production nor signaling through p38, ERK, or PI3K-Akt-mammalian target of rapamycin (mTOR) pathways. Furthermore, such a split regulation of the AHR response was more apparent in GM-CSF-derived macrophages, a finding corroborated at the functional level by decreased CYP1 activity and decreased proinflammatory cytokine production in response to FICZ and LPS. Collectively, our findings identify a role for pattern recognition receptor (PRR) signaling in regulating the AHR response through selective down-regulation of Cyp1 expression in human monocytes and macrophages. © Society for Leukocyte Biology.

Ahr function in lymphocytes: emerging concepts

PubMed Central

Zhou, Liang

2015-01-01

The aryl hydrocarbon receptor (Ahr) is an important regulator of the development and function of both innate and adaptive immune cells through roles associated with Ahr's ability to respond to cellular and dietary ligands. Recent findings have revealed tissue and context-specific functions for Ahr in both homeostasis and in during an immune response. I review these findings here, and integrate them into the current understanding of the mechanisms that regulate Ahr transcription and function. I propose a conceptual framework in which Ahr function is determined by three factors: the amount of Ahr in any given cell, the abundance and potency of Ahr ligands within certain tissues, and the tissue microenvironment wherein Ahr+ cells reside. This complexity emphasizes the necessity cell-type specific genetic approaches towards the study of Ahr function. PMID:26700314

Lithium-Ion Polymer Rechargeable Battery Developed for Aerospace and Military Applications

NASA Technical Reports Server (NTRS)

Hagedorn, orman H.

1999-01-01

A recently completed 3 -year project funded by the Defense Advanced Research Projects Agency (DARPA) under the Technology Reinvestment Program has resulted in the development and scaleup of new lithium-ion polymer battery technology for military and aerospace applications. The contractors for this cost-shared project were Lockheed Martin Missiles & Space and Ultralife Batteries, Inc. The NASA Lewis Research Center provided contract management and technical oversight. The final products of the project were a portable 15-volt (V), 10-ampere-hour (A-hr) military radio battery and a 30-V, 50-A-hr marine/aerospace battery. Lewis will test the 50-A-hr battery. The new lithium-ion polymer battery technology offers a threefold or fourfold reduction in mass and volume, relative to today s commonly used nickel-cadmium, nickel-hydrogen, and nickel-metal hydride batteries. This is of special importance for orbiting satellites. It has been determined for a particular commercial communications satellite that the replacement of 1 kg of battery mass with 1 kg of transponder mass could increase the annual revenue flow by $100 000! Since this lithium-ion polymer technology offers battery mass reductions on the order of hundreds of kilograms for some satellites, the potential revenue increases are impressive.

Mixed-ligand copper(II) complexes activate aryl hydrocarbon receptor AhR and induce CYP1A genes expression in human hepatocytes and human cell lines.

PubMed

Kubešová, Kateřina; Dořičáková, Aneta; Trávníček, Zdeněk; Dvořák, Zdeněk

2016-07-25

The effects of four copper(II) mixed-ligand complexes [Cu(qui1)(L)]NO3·H2O (1-3) and [Cu(qui2)(phen)]NO3 (4), where qui1=2-phenyl-3-hydroxy-4(1H)-quinolinone, Hqui2=2-(4-amino-3,5-dichlorophenyl)-N-propyl-3-hydroxy-4(1H)-quinolinone-7-carboxamide, L=1,10-phenanthroline (phen) (1), 5-methyl-1,10-phenanthroline (mphen) (2), bathophenanthroline (bphen) (3), on transcriptional activities of steroid receptors, nuclear receptors and xenoreceptors have been studied. The complexes (1-4) did not influence basal or ligand-inducible activities of glucocorticoid receptor, androgen receptor, thyroid receptor, pregnane X receptor and vitamin D receptor, as revealed by gene reporter assays. The complexes 1 and 2 dose-dependently induced luciferase activity in stable gene reporter AZ-AhR cell line, and this induction was reverted by resveratrol, indicating involvement of aryl hydrocarbon receptor (AhR) in the process. The complexes 1, 2 and 3 induced CYP1A1 mRNA in LS180 cells and CYP1A1/CYP1A2 in human hepatocytes through AhR. Electrophoretic mobility shift assay EMSA showed that the complexes 1 and 2 transformed AhR in its DNA-binding form. Collectively, we demonstrate that the complexes 1 and 2 activate AhR and induce AhR-dependent genes in human hepatocytes and cancer cell lines. In conclusion, the data presented here might be of toxicological importance, regarding the multiple roles of AhR in human physiology and pathophysiology. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex.

PubMed

Seok, Seung-Hyeon; Lee, Woojong; Jiang, Li; Molugu, Kaivalya; Zheng, Aiping; Li, Yitong; Park, Sanghyun; Bradfield, Christopher A; Xing, Yongna

2017-05-23

The aryl hydrocarbon receptor (AHR) belongs to the PAS (PER-ARNT-SIM) family transcription factors and mediates broad responses to numerous environmental pollutants and cellular metabolites, modulating diverse biological processes from adaptive metabolism, acute toxicity, to normal physiology of vascular and immune systems. The AHR forms a transcriptionally active heterodimer with ARNT (AHR nuclear translocator), which recognizes the dioxin response element (DRE) in the promoter of downstream genes. We determined the crystal structure of the mammalian AHR-ARNT heterodimer in complex with the DRE, in which ARNT curls around AHR into a highly intertwined asymmetric architecture, with extensive heterodimerization interfaces and AHR interdomain interactions. Specific recognition of the DRE is determined locally by the DNA-binding residues, which discriminates it from the closely related hypoxia response element (HRE), and is globally affected by the dimerization interfaces and interdomain interactions. Changes at the interdomain interactions caused either AHR constitutive nuclear localization or failure to translocate to nucleus, underlying an allosteric structural pathway for mediating ligand-induced exposure of nuclear localization signal. These observations, together with the global higher flexibility of the AHR PAS-A and its loosely packed structural elements, suggest a dynamic structural hierarchy for complex scenarios of AHR activation induced by its diverse ligands.

Role of zebrafish cytochrome P450 CYP1C genes in the reduced mesencephalic vein blood flow caused by activation of AHR2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kubota, Akira, E-mail: akubota@whoi.edu; Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543; Stegeman, John J.

2011-06-15

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes various signs of toxicity in early life stages of vertebrates through activation of the aryl hydrocarbon receptor (AHR). We previously reported a sensitive and useful endpoint of TCDD developmental toxicity in zebrafish, namely a decrease in blood flow in the dorsal midbrain, but downstream genes involved in the effect are not known. The present study addressed the role of zebrafish cytochrome P450 1C (CYP1C) genes in association with a decrease in mesencephalic vein (MsV) blood flow. The CYP1C subfamily was recently discovered in fish and includes the paralogues CYP1C1 and CYP1C2, both of which are induced viamore » AHR2 in zebrafish embryos. We used morpholino antisense oligonucleotides (MO or morpholino) to block initiation of translation of the target genes. TCDD-induced mRNA expression of CYP1Cs and a decrease in MsV blood flow were both blocked by gene knockdown of AHR2. Gene knockdown of CYP1C1 by two different morpholinos and CYP1C2 by two different morpholinos, but not by their 5 nucleotide-mismatch controls, was effective in blocking reduced MsV blood flow caused by TCDD. The same CYP1C-MOs prevented reduction of blood flow in the MsV caused by {beta}-naphthoflavone (BNF), representing another class of AHR agonists. Whole-mount in situ hybridization revealed that mRNA expression of CYP1C1 and CYP1C2 was induced by TCDD most strongly in branchiogenic primordia and pectoral fin buds. In situ hybridization using head transverse sections showed that TCDD increased the expression of both CYP1Cs in endothelial cells of blood vessels, including the MsV. These results indicate a potential role of CYP1C1 and CYP1C2 in the local circulation failure induced by AHR2 activation in the dorsal midbrain of the zebrafish embryo. - Research Highlights: > We examine the roles of zebrafish CYP1C1 and CYP1C2 in TCDD developmental toxicity. > TCDD induces mRNA expression of both CYP1Cs in the mesencephalic vein. > Knockdown

Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex

PubMed Central

Lee, Woojong; Jiang, Li; Molugu, Kaivalya; Zheng, Aiping; Li, Yitong; Park, Sanghyun; Bradfield, Christopher A.; Xing, Yongna

2017-01-01

The aryl hydrocarbon receptor (AHR) belongs to the PAS (PER-ARNT-SIM) family transcription factors and mediates broad responses to numerous environmental pollutants and cellular metabolites, modulating diverse biological processes from adaptive metabolism, acute toxicity, to normal physiology of vascular and immune systems. The AHR forms a transcriptionally active heterodimer with ARNT (AHR nuclear translocator), which recognizes the dioxin response element (DRE) in the promoter of downstream genes. We determined the crystal structure of the mammalian AHR–ARNT heterodimer in complex with the DRE, in which ARNT curls around AHR into a highly intertwined asymmetric architecture, with extensive heterodimerization interfaces and AHR interdomain interactions. Specific recognition of the DRE is determined locally by the DNA-binding residues, which discriminates it from the closely related hypoxia response element (HRE), and is globally affected by the dimerization interfaces and interdomain interactions. Changes at the interdomain interactions caused either AHR constitutive nuclear localization or failure to translocate to nucleus, underlying an allosteric structural pathway for mediating ligand-induced exposure of nuclear localization signal. These observations, together with the global higher flexibility of the AHR PAS-A and its loosely packed structural elements, suggest a dynamic structural hierarchy for complex scenarios of AHR activation induced by its diverse ligands. PMID:28396409

Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seok, Seung-Hyeon; Lee, Woojong; Jiang, Li

he aryl hydrocarbon receptor (AHR) belongs to the PAS (PER-ARNT-SIM) family transcription factors and mediates broad responses to numerous environmental pollutants and cellular metabolites, modulating diverse biological processes from adaptive metabolism, acute toxicity, to normal physiology of vascular and immune systems. The AHR forms a transcriptionally active heterodimer with ARNT (AHR nuclear translocator), which recognizes the dioxin response element (DRE) in the promoter of downstream genes. We determined the crystal structure of the mammalian AHR–ARNT heterodimer in complex with the DRE, in which ARNT curls around AHR into a highly intertwined asymmetric architecture, with extensive heterodimerization interfaces and AHR interdomainmore » interactions. Specific recognition of the DRE is determined locally by the DNA-binding residues, which discriminates it from the closely related hypoxia response element (HRE), and is globally affected by the dimerization interfaces and interdomain interactions. Changes at the interdomain interactions caused either AHR constitutive nuclear localization or failure to translocate to nucleus, underlying an allosteric structural pathway for mediating ligand-induced exposure of nuclear localization signal. These observations, together with the global higher flexibility of the AHR PAS-A and its loosely packed structural elements, suggest a dynamic structural hierarchy for complex scenarios of AHR activation induced by its diverse ligands.« less

Aryl hydrocarbon receptor (AhR) a possible target for the treatment of skin disease.

PubMed

Napolitano, Maddalena; Patruno, Cataldo

2018-07-01

Aryl hydrocarbon receptor (AhR) is a transcription factor expressed in all skin cells type. It responds to exogenous and endogenous chemicals by inducing/repressing the expression of several genes with toxic or protective effects in a wide range of species and tissues. In healthy skin, AhR signalling contributes to keratinocytes differentiation, skin barrier function, skin pigmentation, and mediates oxidative stress. In the last years, some studies have shown that AhR seems to be involved in the pathogenesis of some skin diseases, even if the currently available data are contradictory. Indeed, while the blocking the AhR signalling activity could prevent or treat skin cancer, the AhR activation seems to be advantageous for the treatment of inflammatory skin diseases. Therefore, for its multifaceted role in skin diseases, AhR seems to be an attractive therapeutic target. Indeed, recently some molecules have been identified for the prevention of skin cancer and the treatment of inflammatory skin diseases. Copyright © 2018 Elsevier Ltd. All rights reserved.

Human and rodent aryl hydrocarbon receptor (AHR): from mediator of dioxin toxicity to physiologic AHR functions and therapeutic options.

PubMed

Bock, Karl Walter

2017-04-01

Metabolism of aryl hydrocarbons and toxicity of dioxins led to the discovery of the aryl hydrocarbon receptor (AHR). Tremendous advances have been made on multiplicity of AHR signaling and identification of endogenous ligands including the tryptophan metabolites FICZ and kynurenine. However, human AHR functions are still poorly understood due to marked species differences as well as cell-type- and cell context-dependent AHR functions. Observations in dioxin-poisoned individuals may provide hints to physiologic AHR functions in humans. Based on these observations three human AHR functions are discussed: (1) Chemical defence and homeostasis of endobiotics. The AHR variant Val381 in modern humans leads to reduced AHR affinity to aryl hydrocarbons in comparison with Neanderthals and primates expressing the Ala381 variant while affinity to indoles remains unimpaired. (2) Homeostasis of stem/progenitor cells. Dioxins dysregulate homeostasis in sebocyte stem cells. (3) Modulation of immunity. In addition to microbial defence, AHR may be involved in a 'disease tolerance defence pathway'. Further characterization of physiologic AHR functions may lead to therapeutic options.

Role of Sequence Variations in AhR Gene Towards Modulating Smoking Induced Lung Cancer Susceptibility in North Indian Population: A Multiple Interaction Analysis.

PubMed

Budhwar, Sneha; Bahl, Charu; Sharma, Siddharth; Singh, Navneet; Behera, Digambar

2018-05-01

AhR, a ubiquitously expressed ligand-activated transcription factor, upon its encounter with the foreign ligands activates the transcriptional machinery of genes encoding for bio-transformation enzymes like CYP1A1 hence, mediating the metabolism of Poly aromatic hydrocarbons and nitrosamines which account for the maximally found carcinogen in cigarette smoke. Polymorphic variants of AhR play a significant role and are held responsible for disposing the individuals with greater chances of acquiring lung cancer. To study the role of AhR variants (rs2282885, rs10250822, rs7811989, rs2066853) in affect-ing lung cancer susceptibility. 297 cases and 320 controls have been genotyped using PCR-RFLP technique. In order to find out the association, unconditional logistic regression approach was used. To analyze high order in-teractions Multifactor Dimensionality Reduction and Classification and regression tree was used. Subjects carrying the variant genotype for AhR rs7811989 showed a two-fold risk (p=0.007) and a marginal risk was also seen in case of individuals carrying either single or double copy of suscep-tible allele for rs102550822 (p=0.02). Whereas the variant allele for rs2066853 showcased a strong pro-tective effect (p=0.003). SQCC individuals with mutant genotype of rs2066853 also exhibited a protec-tive effect towards lung cancer (OR=0.30, p=0.0013). The association of rs7811989 mutant genotype and rs10250822 mutant genotype was evident especially in smokers as compared to non-smokers. AhR rs2066853 showed a decreased risk in smokers with mutant genotype (p=0.002). MDR approach gave the best interaction model of AhR rs2066853 and smoking (CVC=10/10, prediction error=0.42). AhR polymorphic variations can significantly contribute towards lung cancer predisposi-tion.

Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders

PubMed Central

Busbee, Philip B; Rouse, Michael; Nagarkatti, Mitzi; Nagarkatti, Prakash S

2014-01-01

The aim of this review is to discuss research involving ligands for the aryl hydrocarbon receptor (AhR) and their role in immunomodulation. While activation of the AhR is well known for its ability to regulate the biochemical and toxic effects of environmental chemicals, more recently an exciting discovery has been made indicating that AhR ligation can also regulate T-cell differentiation, specifically through activation of Foxp3+ regulatory T cells (Tregs) and downregulation of the proinflammatory Th17 cells. Such findings have opened new avenues of research on the possibility of targeting the AhR to treat inflammatory and autoimmune diseases. Specifically, this review will discuss the current research involving natural and dietary AhR ligands. In addition, evidence indicating the potential use of these ligands in regulating inflammation in various diseases will be highlighted. The importance of the AhR in immunological processes can be illustrated by expression of this receptor on a majority of immune cell types. In addition, AhR signaling pathways have been reported to influence a number of genes responsible for mediating inflammation and other immune responses. As interest in the AhR and its ligands increases, it seems prudent to consolidate current research on the contributions of these ligands to immune regulation during the course of inflammatory diseases. PMID:23731446

Serotonin is an endogenous regulator of intestinal CYP1A1 via AhR.

PubMed

Manzella, Christopher; Singhal, Megha; Alrefai, Waddah A; Saksena, Seema; Dudeja, Pradeep K; Gill, Ravinder K

2018-04-17

Aryl hydrocarbon receptor (AhR) is a nuclear receptor that controls xenobiotic detoxification via induction of cytochrome P450 1A1 (CYP1A1) and regulates immune responses in the intestine. Metabolites of L-tryptophan activate AhR, which confers protection against intestinal inflammation. We tested the hypothesis that serotonin (5-HT) is an endogenous activator of AhR in intestinal epithelial cells. Treatment of Caco-2 monolayers with 5-HT induced CYP1A1 mRNA in a time- and concentration-dependent manner and also stimulated CYP1A1 activity. CYP1A1 induction by 5-HT was dependent upon uptake via serotonin transporter (SERT). Antagonism of AhR and knockdown of AhR and its binding partner aryl hydrocarbon receptor nuclear translocator (ARNT) attenuated CYP1A1 induction by 5-HT. Activation of AhR was evident by its nuclear translocation after 5-HT treatment and by induction of an AhR-responsive luciferase reporter. In vivo studies showed a dramatic decrease in CYP1A1 expression and other AhR target genes in SERT KO ileal mucosa by microarray analysis. These results suggest that intracellular accumulation of 5-HT via SERT induces CYP1A1 expression via AhR in intestinal epithelial cells, and SERT deficiency in vivo impairs activation of AhR. Our studies provide a novel link between the serotonergic and AhR pathways which has implications in xenobiotic metabolism and intestinal inflammation.

Antioxidant Artemisia princeps Extract Enhances the Expression of Filaggrin and Loricrin via the AHR/OVOL1 Pathway.

PubMed

Hirano, Akiko; Goto, Masashi; Mitsui, Tsukasa; Hashimoto-Hachiya, Akiko; Tsuji, Gaku; Furue, Masutaka

2017-09-11

The Japanese mugwort, Artemisia princeps ( yomogi in Japanese), has anti-inflammatory and antioxidant effects. Skin care products containing Artemisia princeps extract (APE) are known to improve dry skin symptoms in atopic dermatitis. Atopic dry skin is associated with a marked reduction of skin barrier proteins, such as filaggrin (FLG) and loricrin (LOR). Recently, aryl hydrocarbon receptor (AHR), and its downstream transcription factor OVO-like 1 (OVOL1), have been shown to regulate the gene expression of FLG and LOR. The focus of this paper is to evaluate the effects of APE on the AHR/OVOL1/FLG or LOR pathway since they have remained unknown to this point. We first demonstrated that non-cytotoxic concentrations of APE significantly upregulated antioxidant enzymes, NAD(P)H dehydrogenase quinone 1 and heme oxygenase 1, in human keratinocytes. Even at these low concentrations, APE induced nuclear translocation of AHR and significantly upregulated CYP1A1 (a specific target gene for AHR activation), FLG , and LOR expression. AHR knockdown downregulated OVOL1 expression. The APE-induced upregulation of FLG and LOR was canceled in keratinocytes with AHR or OVOL1 knockdown. In conclusion, antioxidant APE is a potent phytoextract that upregulates FLG and LOR expression in an AHR/OVOL1-dependent manner and this may underpin the barrier-repairing effects of APE in treating atopic dry skin.

Antioxidant Artemisia princeps Extract Enhances the Expression of Filaggrin and Loricrin via the AHR/OVOL1 Pathway

PubMed Central

Hirano, Akiko; Goto, Masashi; Mitsui, Tsukasa; Hashimoto-Hachiya, Akiko; Tsuji, Gaku; Furue, Masutaka

2017-01-01

The Japanese mugwort, Artemisia princeps (yomogi in Japanese), has anti-inflammatory and antioxidant effects. Skin care products containing Artemisia princeps extract (APE) are known to improve dry skin symptoms in atopic dermatitis. Atopic dry skin is associated with a marked reduction of skin barrier proteins, such as filaggrin (FLG) and loricrin (LOR). Recently, aryl hydrocarbon receptor (AHR), and its downstream transcription factor OVO-like 1 (OVOL1), have been shown to regulate the gene expression of FLG and LOR. The focus of this paper is to evaluate the effects of APE on the AHR/OVOL1/FLG or LOR pathway since they have remained unknown to this point. We first demonstrated that non-cytotoxic concentrations of APE significantly upregulated antioxidant enzymes, NAD(P)H dehydrogenase quinone 1 and heme oxygenase 1, in human keratinocytes. Even at these low concentrations, APE induced nuclear translocation of AHR and significantly upregulated CYP1A1 (a specific target gene for AHR activation), FLG, and LOR expression. AHR knockdown downregulated OVOL1 expression. The APE-induced upregulation of FLG and LOR was canceled in keratinocytes with AHR or OVOL1 knockdown. In conclusion, antioxidant APE is a potent phytoextract that upregulates FLG and LOR expression in an AHR/OVOL1-dependent manner and this may underpin the barrier-repairing effects of APE in treating atopic dry skin. PMID:28892018

Feedback control of AHR signalling regulates intestinal immunity.

PubMed

Schiering, Chris; Wincent, Emma; Metidji, Amina; Iseppon, Andrea; Li, Ying; Potocnik, Alexandre J; Omenetti, Sara; Henderson, Colin J; Wolf, C Roland; Nebert, Daniel W; Stockinger, Brigitta

2017-02-09

The aryl hydrocarbon receptor (AHR) recognizes xenobiotics as well as natural compounds such as tryptophan metabolites, dietary components and microbiota-derived factors, and it is important for maintenance of homeostasis at mucosal surfaces. AHR activation induces cytochrome P4501 (CYP1) enzymes, which oxygenate AHR ligands, leading to their metabolic clearance and detoxification. Thus, CYP1 enzymes have an important feedback role that curtails the duration of AHR signalling, but it remains unclear whether they also regulate AHR ligand availability in vivo. Here we show that dysregulated expression of Cyp1a1 in mice depletes the reservoir of natural AHR ligands, generating a quasi AHR-deficient state. Constitutive expression of Cyp1a1 throughout the body or restricted specifically to intestinal epithelial cells resulted in loss of AHR-dependent type 3 innate lymphoid cells and T helper 17 cells and increased susceptibility to enteric infection. The deleterious effects of excessive AHR ligand degradation on intestinal immune functions could be counter-balanced by increasing the intake of AHR ligands in the diet. Thus, our data indicate that intestinal epithelial cells serve as gatekeepers for the supply of AHR ligands to the host and emphasize the importance of feedback control in modulating AHR pathway activation.

INSIGHTS FROM AHR AND ARNT GENE KNOCKOUT STUDIES REGARDING RESPONSES TO TCDD AND REGULATION OF NORMAL EMBRYONIC DEVELOPMENT

EPA Science Inventory

The aryl hydrocarbon receptor (AhR) and the AhR nuclear translocator (ARNT) are members of the Per-ARNT-Sim (PAS) family of proteins. The AhR binds members of the chemical family that includes dioxins, furans and coplanar polychlorinated biphenyls (PCBs). A ligand-AhR-ARNT comp...

Cross-regulatory circuit between AHR and microbiota.

PubMed

Ji, Jian; Qu, Hao

2018-01-29

The gut microbes have a close symbiotic relationship with their host. Interactions between host and the microbiota affect the nutritional, immunological, and physiological status of the host. The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that mediates the toxicity of xenobiotics. Recently, the relationship between the gut microbiota and AHR has attracted the attention of many researchers. The AHR influences the intestinal microbiota population and mediates host-microbe homeostasis. Interestingly, the gut microbiota also produces ligands of AHR from bacterial metabolism and thereby activates the AHR signaling pathway. This review presents current knowledge of the cross-regulatory circuit between the AHR and intestinal microbiota. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effects of 4-nitrophenol on expression of the ER-α and AhR signaling pathway-associated genes in the small intestine of rats.

PubMed

Tang, Juan; Song, Meiyan; Watanabe, Gen; Nagaoka, Kentaro; Rui, Xiaoli; Li, ChunMei

2016-09-01

4-Nitrophenol (PNP) is a persistent organic pollutant that was proven to be an environmental endocrine disruptor. The aim of this study was to evaluate the role of the estrogen receptor-α (ER-α) and aryl hydrocarbon receptor (AhR) signaling pathway in regulating the damage response to PNP in the small intestine of rats. Wistar-Imamichi male rats (21 d) were randomly divided into two groups: the control group and PNP group. Each group had three processes that were gavaged with PNP or vehicle daily: single dose (1 d), repeated dose (3 consecutive days) (3 d), and repeated dose with recovery (3 consecutive days and 3 recovery days) (6 d). The weight of the body, the related viscera, and small intestine were examined. Histological parameters of the small intestine and the quantity of mucus proteins secreted by small goblet cells were determined using HE staining and PAS staining. The mRNA expression of AhR, ER-α, CYP1A1, and GST was measured by real-time qPCR. In addition, we also analyzed the AhR, ER-α, and CYP1A1 expression in the small intestine by immunohistochemical staining. The small intestines histologically changed in the PNP-treated rat and the expression of AhR, CYP1A1, and GST was increased. While ER-α was significantly decreased in the small intestine, simultaneously, when rats were exposed to a longer PNP treatment, the damages disappeared. Our results demonstrate that PNP has an effect on the expression of AhR signaling pathway genes, AhR, CYP1A1, and GST, and ER-α in the rat small intestine. Copyright © 2016 Elsevier Ltd. All rights reserved.

The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells.

PubMed

Ghotbaddini, Maryam; Powell, Joann B

2015-07-06

The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR). TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR) expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models.

The aryl hydrocarbon receptor-mediated disruption of vitellogenin synthesis in the fish liver: Cross-talk between AHR- and ERα-signalling pathways

PubMed Central

Bemanian, Vahid; Male, Rune; Goksøyr, Anders

2004-01-01

Background In the fish liver, the synthesis of egg yolk protein precursor vitellogenin (VTG) is under control of the estrogen receptor alpha (ERα). Environmental contaminants such as 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) are suspected to have antiestrogenic effects. The aryl hydrocarbon receptor (AHR) is the initial cellular target for TCDD and related compounds. The AHR is a ligand-activated transcription factor that stimulates the expression of the genes encoding xenobiotic metabolizing enzymes, such as cytochrome P450 1A (CYP1A). In this study, the effects of activation of AHR on the hepatic expression of VTG and ERα genes, in primary cultured salmon hepatocytes, have been investigated. Results The expression of the genes encoding VTG and ERα were strongly induced by 17β-estradiol (E2). However, the expression of VTG was disrupted by exposure of the cells to TCDD while CYP1A expression was enhanced. The effect of TCDD on VTG and CYP1A expression was annulled by the AHR-inhibitor α-naphthoflavone. Furthermore, exposure of the cells to TCDD abolished E2-induced accumulation of ERα mRNA. The AHR-mediated inhibitory effects on the expression of the VTG and ERα genes may occur at transcriptional and/or post-transcriptional levels. Nuclear run-off experiments revealed that simultaneous exposure of the cells to E2 and TCDD strongly inhibited the initiation of transcription of the VTG and ERα genes. In addition, inhibition of RNA synthesis by actinomycin D treatment showed that post-transcriptional levels of VTG and ERα mRNAs were not significantly altered upon treatment of the cells with TCDD. These results suggested that activation of AHR may inhibit the transactivation capacity of the ERα. Further, electrophoretic mobility shift assays using nuclear extracts prepared from cells treated for one or two hours with E2, alone or in mixture with TCDD, showed a strong reduction in the DNA binding activities upon TCDD treatment. These results also suggested

Crosstalk between AhR and wnt/β-catenin signal pathways in the cardiac developmental toxicity of PM2.5 in zebrafish embryos.

PubMed

Zhang, Hang; Yao, Yugang; Chen, Yang; Yue, Cong; Chen, Jiahong; Tong, Jian; Jiang, Yan; Chen, Tao

2016-04-29

Recent studies have shown an association between congenital heart defects and air fine particle matter (PM2.5), but the molecular mechanisms remain elusive. It is well known that a number of organic compounds in PM2.5 can act as AhR agonists, and activation of AhR can antagonize Wnt/β-catenin signaling. Therefore, we hypothesized that PM2.5 could activate AhR and then repress the expression of wnt/β-catenin targeted genes essential for cardiogenesis, resulting in heart defects. To test this hypothesis, we investigated the effects of extractable organic matter (EOM) from PM2.5 on AhR and Wnt/β-catenin signal pathways in zebrafish embryos. We confirmed that EOM could cause malformations in the heart and decreased heart rate in zebrafish embryos at 72hpf, and found that the EOM-induced heart defects were rescued in embryos co-exposed with EOM plus AhR antagonist CH223191 or β-catenin agonist CHIR99021. We further found that EOM had increased the expression levels of AhR targeted genes (Cyp1a1, Cyp1b1 and Ahrra) and reduced the mRNA levels of β-catenin targeted genes (axin2, nkx2.5 and sox9b). The mRNA expression level of Rspo2, a β-catenin upstream gene, was also decreased in embryos exposed to EOM. Supplementation with CH223191 or CHIR99021 attenuated most of the EOM-induced expression changes of genes involved in both AhR and wnt/β-catenin signal pathways. However, the mRNA expression level of AhR inhibitor Ahrrb, which did not change by EOM treatment alone, was increased in embryos co-exposed to EOM plus CH223191 or CHIR99021. We conclude that the activation of AhR by EOM from PM2.5 might repress wnt/β-catenin signaling, leading to heart defects in zebrafish embryos. Furthermore, our results indicate that the cardiac developmental toxicity of PM2.5 might be prevented by targeting AhR or wnt/β-catenin signaling. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin.

PubMed

Hidaka, Takanori; Ogawa, Eisaku; Kobayashi, Eri H; Suzuki, Takafumi; Funayama, Ryo; Nagashima, Takeshi; Fujimura, Taku; Aiba, Setsuya; Nakayama, Keiko; Okuyama, Ryuhei; Yamamoto, Masayuki

2017-01-01

Atopic dermatitis is increasing worldwide in correlation with air pollution. Various organic components of pollutants activate the transcription factor AhR (aryl hydrocarbon receptor). Through the use of AhR-CA mice, whose keratinocytes express constitutively active AhR and that develop atopic-dermatitis-like phenotypes, we identified Artn as a keratinocyte-specific AhR target gene whose product (the neurotrophic factor artemin) was responsible for epidermal hyper-innervation that led to hypersensitivity to pruritus. The activation of AhR via air pollutants induced expression of artemin, alloknesis, epidermal hyper-innervation and inflammation. AhR activation and ARTN expression were positively correlated in the epidermis of patients with atopic dermatitis. Thus, AhR in keratinocytes senses environmental stimuli and elicits an atopic-dermatitis pathology. We propose a mechanism of air-pollution-induced atopic dermatitis via activation of AhR.

Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis

PubMed Central

van den Bogaard, Ellen H.; Bergboer, Judith G.M.; Vonk-Bergers, Mieke; van Vlijmen-Willems, Ivonne M.J.J.; Hato, Stanleyson V.; van der Valk, Pieter G.M.; Schröder, Jens Michael; Joosten, Irma; Zeeuwen, Patrick L.J.M.; Schalkwijk, Joost

2013-01-01

Topical application of coal tar is one of the oldest therapies for atopic dermatitis (AD), a T helper 2 (Th2) lymphocyte–mediated skin disease associated with loss-of-function mutations in the skin barrier gene, filaggrin (FLG). Despite its longstanding clinical use and efficacy, the molecular mechanism of coal tar therapy is unknown. Using organotypic skin models with primary keratinocytes from AD patients and controls, we found that coal tar activated the aryl hydrocarbon receptor (AHR), resulting in induction of epidermal differentiation. AHR knockdown by siRNA completely abrogated this effect. Coal tar restored filaggrin expression in FLG-haploinsufficient keratinocytes to wild-type levels, and counteracted Th2 cytokine–mediated downregulation of skin barrier proteins. In AD patients, coal tar completely restored expression of major skin barrier proteins, including filaggrin. Using organotypic skin models stimulated with Th2 cytokines IL-4 and IL-13, we found coal tar to diminish spongiosis, apoptosis, and CCL26 expression, all AD hallmarks. Coal tar interfered with Th2 cytokine signaling via dephosphorylation of STAT6, most likely due to AHR-regulated activation of the NRF2 antioxidative stress pathway. The therapeutic effect of AHR activation herein described opens a new avenue to reconsider AHR as a pharmacological target and could lead to the development of mechanism-based drugs for AD. PMID:23348739

Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis.

PubMed

van den Bogaard, Ellen H; Bergboer, Judith G M; Vonk-Bergers, Mieke; van Vlijmen-Willems, Ivonne M J J; Hato, Stanleyson V; van der Valk, Pieter G M; Schröder, Jens Michael; Joosten, Irma; Zeeuwen, Patrick L J M; Schalkwijk, Joost

2013-02-01

Topical application of coal tar is one of the oldest therapies for atopic dermatitis (AD), a T helper 2 (Th2) lymphocyte-mediated skin disease associated with loss-of-function mutations in the skin barrier gene, filaggrin (FLG). Despite its longstanding clinical use and efficacy, the molecular mechanism of coal tar therapy is unknown. Using organotypic skin models with primary keratinocytes from AD patients and controls, we found that coal tar activated the aryl hydrocarbon receptor (AHR), resulting in induction of epidermal differentiation. AHR knockdown by siRNA completely abrogated this effect. Coal tar restored filaggrin expression in FLG-haploinsufficient keratinocytes to wild-type levels, and counteracted Th2 cytokine-mediated downregulation of skin barrier proteins. In AD patients, coal tar completely restored expression of major skin barrier proteins, including filaggrin. Using organotypic skin models stimulated with Th2 cytokines IL-4 and IL-13, we found coal tar to diminish spongiosis, apoptosis, and CCL26 expression, all AD hallmarks. Coal tar interfered with Th2 cytokine signaling via dephosphorylation of STAT6, most likely due to AHR-regulated activation of the NRF2 antioxidative stress pathway. The therapeutic effect of AHR activation herein described opens a new avenue to reconsider AHR as a pharmacological target and could lead to the development of mechanism-based drugs for AD.

Dioxin induces Ahr-dependent robust DNA demethylation of the Cyp1a1 promoter via Tdg in the mouse liver.

PubMed

Amenya, Hesbon Z; Tohyama, Chiharu; Ohsako, Seiichiroh

2016-10-07

The aryl hydrocarbon receptor (Ahr) is a highly conserved nuclear receptor that plays an important role in the manifestation of toxicity induced by polycyclic aromatic hydrocarbons. As a xenobiotic sensor, Ahr is involved in chemical biotransformation through activation of drug metabolizing enzymes. The activated Ahr cooperates with coactivator complexes to induce epigenetic modifications at target genes. Thus, it is conceivable that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent Ahr ligand, may elicit robust epigenetic changes in vivo at the Ahr target gene cytochrome P450 1a1 (Cyp1a1). A single dose of TCDD administered to adult mice induced Ahr-dependent CpG hypomethylation, changes in histone modifications, and thymine DNA glycosylase (Tdg) recruitment at the Cyp1a1 promoter in the liver within 24 hrs. These epigenetic changes persisted until 40 days post-TCDD treatment and there was Cyp1a1 mRNA hyperinduction upon repeat administration of TCDD at this time-point. Our demethylation assay using siRNA knockdown and an in vitro methylated plasmid showed that Ahr, Tdg, and the ten-eleven translocation methyldioxygenases Tet2 and Tet3 are required for the TCDD-induced DNA demethylation. These results provide novel evidence of Ahr-driven active DNA demethylation and epigenetic memory. The epigenetic alterations influence response to subsequent chemical exposure and imply an adaptive mechanism to xenobiotic stress.

Dioxin induces Ahr-dependent robust DNA demethylation of the Cyp1a1 promoter via Tdg in the mouse liver

NASA Astrophysics Data System (ADS)

Amenya, Hesbon Z.; Tohyama, Chiharu; Ohsako, Seiichiroh

2016-10-01

The aryl hydrocarbon receptor (Ahr) is a highly conserved nuclear receptor that plays an important role in the manifestation of toxicity induced by polycyclic aromatic hydrocarbons. As a xenobiotic sensor, Ahr is involved in chemical biotransformation through activation of drug metabolizing enzymes. The activated Ahr cooperates with coactivator complexes to induce epigenetic modifications at target genes. Thus, it is conceivable that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent Ahr ligand, may elicit robust epigenetic changes in vivo at the Ahr target gene cytochrome P450 1a1 (Cyp1a1). A single dose of TCDD administered to adult mice induced Ahr-dependent CpG hypomethylation, changes in histone modifications, and thymine DNA glycosylase (Tdg) recruitment at the Cyp1a1 promoter in the liver within 24 hrs. These epigenetic changes persisted until 40 days post-TCDD treatment and there was Cyp1a1 mRNA hyperinduction upon repeat administration of TCDD at this time-point. Our demethylation assay using siRNA knockdown and an in vitro methylated plasmid showed that Ahr, Tdg, and the ten-eleven translocation methyldioxygenases Tet2 and Tet3 are required for the TCDD-induced DNA demethylation. These results provide novel evidence of Ahr-driven active DNA demethylation and epigenetic memory. The epigenetic alterations influence response to subsequent chemical exposure and imply an adaptive mechanism to xenobiotic stress.

Simultaneous inhibition of aryl hydrocarbon receptor (AhR) and Src abolishes androgen receptor signaling.

PubMed

Ghotbaddini, Maryam; Cisse, Keyana; Carey, Alexis; Powell, Joann B

2017-01-01

Altered c-Src activity has been strongly implicated in the development, growth, progression, and metastasis of human cancers including prostate cancer. Src is known to regulate several biological functions of tumor cells, including proliferation. There are several Src inhibitors under evaluation for clinical effectiveness but have shown little activity in monotherapy trials of solid tumors. Combination studies are being explored by in vitro analysis and in clinical trials. Here we investigate the effect of simultaneous inhibition of the aryl hydrocarbon receptor (AhR) and Src on androgen receptor (AR) signaling in prostate cancer cells. AhR has also been reported to interact with the Src signaling pathway during prostate development. c-Src protein kinase is associated with the AhR complex in the cytosol and upon ligand binding to AhR, c-Src is activated and released from the complex. AhR has also been shown to regulate AR signaling which remains functionally important in the development and progression of prostate cancer. We provide evidence that co-inhibition of AhR and Src abolish AR activity. Evaluation of total protein and cellular fractions revealed decreased pAR expression and AR nuclear localization. Assays utilizing an androgen responsive element (ARE) and qRT-PCR analysis of AR genes revealed decreased AR promoter activity and transcriptional activity in the presence of both AhR and Src inhibitors. Furthermore, co-inhibition of AhR and Src reduced the growth of prostate cancer cells compared to individual treatments. Several studies have revealed that AhR and Src individually inhibit cellular proliferation. However, this study is the first to suggest simultaneous inhibition of AhR and Src to inhibit AR signaling and prostate cancer cell growth.

The aryl hydrocarbon receptor (AhR) mediates resistance to apoptosis induced in breast cancer cells.

PubMed

Bekki, Kanae; Vogel, Helena; Li, Wen; Ito, Tomohiro; Sweeney, Colleen; Haarmann-Stemmann, Thomas; Matsumura, Fumio; Vogel, Christoph F A

2015-05-01

The aryl hydrocarbon receptor (AhR) is well known as a ligand binding transcription factor regulating various biological effects. Previously we have shown that long-term exposure to estrogen in breast cancer cells caused not only down regulation of estrogen receptor (ER) but also overexpression of AhR. The AhR interacts with several cell signaling pathways associated with induction of tyrosine kinases, cytokines and growth factors which may support the survival roles of AhR escaping from apoptosis elicited by a variety of apoptosis inducing agents in breast cancer. In this study, we studied the anti-apoptotic role of AhR in different breast cancer cells when apoptosis was induced by exposure to UV light and chemotherapeutic agents. Activation of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in AhR overexpressing breast cancer cells effectively suppressed the apoptotic response induced by UV-irradiation, doxorubicin, lapatinib and paclitaxel. The anti-apoptotic response of TCDD was uniformly antagonized by the treatment with 3'methoxy-4'nitroflavone (MNF), a specific antagonist of AhR. TCDD's survival action of apoptosis was accompanied with the induction of well-known inflammatory genes, such as cyclooxygenase-2 (COX-2) and NF-κB subunit RelB. Moreover, TCDD increased the activity of the immunosuppressive enzyme indoleamine 2, 3-dioxygenase (IDO), which metabolizes tryptophan to kynurenine (Kyn) and mediates tumor immunity. Kyn also acts as an AhR ligand like TCDD, and kyn induced an anti-apoptotic response in breast cancer cells. Accordingly, our present study suggests that AhR plays a pivotal role in the development of breast cancer via the suppression of apoptosis, and provides an idea that the use of AhR antagonists with chemotherapeutic agents may effectively synergize the elimination of breast cancer cells. Copyright © 2014 Elsevier Inc. All rights reserved.

High Capacity Battery Cell Flight Qualified

NASA Technical Reports Server (NTRS)

McKissock, Barbara I.

1997-01-01

The High Capacity Battery Cell project is an effort equally funded by the NASA Lewis Research Center and Hughes Space and Communications Company (a unit of Hughes Aircraft Company) to develop and flight qualify a higher capacity nickel hydrogen battery for continuing use on commercial spacecraft. The larger diameter, individual pressure vessel cell will provide approximately twice the power, while occupying the same volume, as the current state-of-the-art nickel hydrogen cell. These cells are also anticipated to reduce battery cost by 20 percent. The battery is currently booked for use on 26 spacecraft, with the first flight scheduled in 1997. A strong requirement for batteries with higher power levels (6 to 12 kW), long life, and reduced cost was identified in studies of the needs of commercial communications spacecraft. With the design developed in this effort, the higher power level was accommodated without having to modify the rest of the existing spacecraft bus. This design scaled-up the existing state-of-the-art nickel hydrogen battery cell from a 3.5-in., 50-Ahr cell to a 5.5-in., 350-Ahr cell. An improvement in cycle life was also achieved by the use of the 26-percent KOH electrolyte design developed by NASA Lewis. The cell design was completed, and flight batteries were built and flight qualified by Hughes Space and Communications Company with input from NASA Lewis. Two batteries were shipped in September 1996 to undergo life cycle testing under the purview of NASA Lewis.

AHR and CYP1A expression link historical contamination events to modern day developmental effects in the American alligator.

PubMed

Hale, Matthew D; Galligan, Thomas M; Rainwater, Thomas R; Moore, Brandon C; Wilkinson, Philip M; Guillette, Louis J; Parrott, Benjamin B

2017-11-01

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that initiates a transcriptional pathway responsible for the expression of CYP1A subfamily members, key to the metabolism of xenobiotic compounds. Toxic planar halogenated aromatic hydrocarbons, including dioxin and PCBs, are capable of activating the AHR, and while dioxin and PCB inputs into the environment have been dramatically curbed following strict regulatory efforts in the United States, they persist in the environment and exposures remain relevant today. Little is known regarding the effects that long-term chronic exposures to dioxin or dioxin-like compounds might have on the development and subsequent health of offspring from exposed individuals, nor is much known regarding AHR expression in reptilians. Here, we characterize AHR and CYP1A gene expression in embryonic and juvenile specimen of a long-lived, apex predator, the American alligator (Alligator mississippiensis), and investigate variation in gene expression profiles in offspring collected from sites conveying differential exposures to environmental contaminants. Both age- and tissue-dependent patterning of AHR isoform expression are detected. We characterize two downstream transcriptional targets of the AHR, CYP1A1 and CYP1A2, and describe conserved elements of their genomic architecture. When comparisons across different sites are made, hepatic expression of CYP1A2, a direct target of the AHR, appears elevated in embryos from a site associated with a dioxin point source and previously characterized PCB contamination. Elevated CYP1A2 expression is not persistent, as site-specific variation was absent in juveniles originating from field-collected eggs but reared under lab conditions. Our results illustrate the patterning of AHR gene expression in a long-lived environmental model species, and indicate a potential contemporary influence of historical contamination. This research presents a novel opportunity to link

AhR transcriptional activity in serum of Inuits across Greenlandic districts

PubMed Central

Long, Manhai; Deutch, Bente; Bonefeld-Jorgensen, Eva C

2007-01-01

Background Human exposure to lipophilic persistent organic pollutants (POPs) including polychlorinated dibenzo-p-dioxins/furans (PCDDs/PCDFs), polychlorinated biphenyls (PCBs) and organochlorine pesticide is ubiquitous. The individual is exposed to a complex mixture of POPs being life-long beginning during critical developmental windows. Exposure to POPs elicits a number of species- and tissue-specific toxic responses, many of which involve the aryl hydrocarbon receptor (AhR). The aim of this study was to compare the actual level of integrated AhR transcriptional activity in the lipophilic serum fraction containing the actual POP mixture among Inuits from different districts in Greenland, and to evaluate whether the AhR transactivity is correlated to the bio-accumulated POPs and/or lifestyle factors. Methods The study included 357 serum samples from the Greenlandic districts: Nuuk and Sisimiut (South West Coast), Qaanaaq (North Coast) and Tasiilaq (East Coast). The bio-accumulated serum POPs were extracted by ethanol: hexane and clean-up on Florisil columns. Effects of the serum extract on the AhR transactivity was determined using the Hepa 1.12cR mouse hepatoma cell line carrying an AhR-luciferase reporter gene, and the data was evaluated for possible association to the serum levels of 14 PCB congeners, 10 organochlorine pesticide residues and/or lifestyle factors. Results In total 85% of the Inuit samples elicited agonistic AhR transactivity in a district dependent pattern. The median level of the AhR-TCDD equivalent (AhR-TEQ) of the separate genders was similar in the different districts. For the combined data the order of the median AhR-TEQ was Tasiilaq > Nuuk ≥ Sisimiut > Qaanaaq possibly being related to the different composition of POPs. In overall, the AhR transactivity was inversely correlated to the levels of sum POPs, age and/or intake of marine food. Conclusion i) We observed that the proportion of dioxin like (DL) compounds in the POP mixture was the

From the Cover: Development and Application of a Dual Rat and Human AHR Activation Assay.

PubMed

Brown, Martin R; Garside, Helen; Thompson, Emma; Atwal, Saseela; Bean, Chloe; Goodall, Tony; Sullivan, Michael; Graham, Mark J

2017-12-01

Significant prolonged aryl hydrocarbon receptor (AHR) activation, classically exhibited following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin, can cause a variety of undesirable toxicological effects. Novel pharmaceutical chemistries also have the potential to cause activation of AHR and consequent toxicities in pre-clinical species and man. Previous methods either employed relatively expensive and low-throughput primary hepatocyte dosing with PCR endpoint, or low resolution overexpressing reporter gene assays. We have developed, validated and applied an in vitro microtitre plate imaging-based medium throughput screening assay for the assessment of endogenous species-specific AHR activation potential via detection of induction of the surrogate transcriptional target Cytochrome P450 CYP1A1. Routine testing of pharmaceutical drug development candidate chemistries using this assay can influence the chemical design process and highlight AHR liabilities. This assay should be introduced such that human AHR activation liability is flagged early for confirmatory testing. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Lithium-thionyl chloride battery

NASA Astrophysics Data System (ADS)

Wong, D.; Bowden, W.; Hamilton, N.; Cubbison, D.; Dey, A. N.

1981-04-01

The main objective is to develop, fabricate, test, and deliver safe high rate lithium-thionyl chloride batteries for various U.S. Army applications such as manpack ratios and GLLD Laser Designators. We have devoted our efforts in the following major areas: (1) Optimization of the spirally wound D cell for high rate applications, (2) Development of a 3 inch diameter flat cylindrical cell for the GLLD laser designator application, and (3) Investigation of the reduction mechanism of SOCl2. The rate capability of the spirally wound D cell previously developed by us has been optimized for both the manpack radio (BA5590) battery and GLLD laser designator battery application in this program. A flat cylindrical cell has also been developed for the GLLD laser designator application. It is 3 inches in diameter and 0.9 inch in height with extremely low internal cell impedance that minimizes cell heating and polarization on the GLLD load. Typical cell capacity was found to be 18.0-19.0 Ahr with a few cells delivering up to about 21.0 Ahr on the GLLD test load. Study of the reduction mechanism of SOCl2 using electrochemical and spectroscopic techniques has also been carried out in this program which may be directly relevant to the intrinsic safety of the system.

Prototype Lithium-Ion Battery Developed for Mars 2001 Lander

NASA Technical Reports Server (NTRS)

Manzo, Michelle A.

2000-01-01

In fiscal year 1997, NASA, the Jet Propulsion Laboratory, and the U.S. Air Force established a joint program to competitively develop high-power, rechargeable lithium-ion battery technology for aerospace applications. The goal was to address Department of Defense and NASA requirements not met by commercial battery developments. Under this program, contracts have been awarded to Yardney Technical Products, Eagle- Picher Technologies, LLC, BlueStar Advanced Technology Corporation, and SAFT America, Inc., to develop cylindrical and prismatic cell and battery systems for a variety of NASA and U.S. Air Force applications. The battery systems being developed range from low-capacity (7 to 20 A-hr) and low-voltage (14 to 28 V) systems for planetary landers and rovers to systems for aircraft that require up to 270 V and for Unmanned Aerial Vehicles that require capacities up to 200 A-hr. Low-Earth-orbit and geosynchronousorbit spacecraft pose additional challenges to system operation with long cycle life (>30,000 cycles) and long calendar life (>10 years), respectively.

Regulation of subcellular localization of the Aryl Hydrocarbon Receptor (AhR)

USGS Publications Warehouse

Richter, Catherine A.; Tillitt, Donald E.; Hannink, Mark

2001-01-01

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity of dioxin and other xenobiotics. In the absence of exogenous ligand, AhR is cytosolic. We investigated how AhR is retained in the cytosol and how dioxin induces AhR to move to the nucleus. Disruption of nuclear export of AhR by the nuclear export inhibitor leptomycin B (LMB) or by mutation of the AhR nuclear export signal resulted in nuclear accumulation of AhR in the absence of exogenous ligand. Mutation of the AhR nuclear localization signal resulted in defects in nuclear import of AhR in both the presence and the absence of exogenous ligand. Dioxin treatment caused a more rapid accumulation of AhR in the nucleus than LMB treatment. In the presence of both dioxin and LMB, nuclear accumulation of AhR was more rapid than in the presence of dioxin alone. Our results show that AhR shuttles between the nucleus and the cytosol in the absence of exogenous ligand. Binding of ligand induces an increase in the rate of nuclear import of AhR but does not eliminate nuclear export of AhR.

AHR2 morpholino knockdown reduces the toxicity of total particulate matter to zebrafish embryos

DOE Office of Scientific and Technical Information (OSTI.GOV)

Massarsky, Andrey, E-mail: andrey.massarsky@duke.e

The zebrafish embryo has been proposed as a ‘bridge model’ to study the effects of cigarette smoke on early development. Previous studies showed that exposure to total particulate matter (TPM) led to adverse effects in developing zebrafish, and suggested that the antioxidant and aryl hydrocarbon receptor (AHR) pathways play important roles. This study investigated the roles of these two pathways in mediating TPM toxicity. The study consisted of four experiments. In experiment I, zebrafish embryos were exposed from 6 h post fertilization (hpf) until 96 hpf to TPM{sub 0.5} and TPM{sub 1.0} (corresponding to 0.5 and 1.0 μg/mL equi-nicotine units)more » in the presence or absence of an antioxidant (N-acetyl cysteine/NAC) or a pro-oxidant (buthionine sulfoximine/BSO). In experiment II, TPM exposures were performed in embryos that were microinjected with nuclear factor erythroid 2-related factor 2 (Nrf2), AHR2, cytochrome P450 1A (CYP1A), or CYP1B1 morpholinos, and deformities were assessed. In experiment III, embryos were exposed to TPM, and embryos/larvae were collected at 24, 48, 72, and 96 hpf to assess several genes associated with the antioxidant and AHR pathways. Lastly, experiment IV assessed the activity and protein levels of CYP1A and CYP1B1 after exposure to TPM. We demonstrate that the incidence of TPM-induced deformities was generally not affected by NAC/BSO treatments or Nrf2 knockdown. In contrast, AHR2 knockdown reduced, while CYP1A or CYP1B1 knockdowns elevated the incidence of some deformities. Moreover, as shown by gene expression the AHR pathway, but not the antioxidant pathway, was induced in response to TPM exposure, providing further evidence for its importance in mediating TPM toxicity. - Highlights: • Total particulate matter (TPM) is the particulate phase of cigarette smoke. • Zebrafish is proposed as a ‘bridge model’ to study the effects of TPM. • We investigate the roles of antioxidant and aryl hydrocarbon receptor (AHR

The aryl hydrocarbon receptor (AHR) transcription factor regulates megakaryocytic polyploidization

PubMed Central

Lindsey, Stephan; T. Papoutsakis, Eleftherios

2012-01-01

Summary We propose that the aryl hydrocarbon receptor (AHR) is a novel transcriptional regulator of megakaryopoietic polyploidization. Functional evidence was obtained that AHR impacts in vivo megakaryocytic differentiation and maturation; compared to wild-type mice, AHR-null mice had lower platelet counts, fewer numbers of newly synthesized platelets, increased bleeding times and lower-ploidy megakaryocytes (Mks). AHR mRNA increased 3·6-fold during ex vivo megakaryocytic differentiation, but reduced or remained constant during parallel isogenic granulocytic or erythroid differentiation. We interrogated the role of AHR in megakaryopoiesis using a validated Mk model of megakaryopoiesis, the human megakaryoblastic leukaemia CHRF cell line. Upon CHRF Mk differentiation, AHR mRNA and protein levels increased, AHR protein shifted from the cytoplasm to the nucleus and AHR binding to its consensus DNA binding sequence increased. Protein and mRNA levels of the AHR transcriptional target HES1 also increased. Mk differentiation of CHRF cells where AHR or HES1 was knocked-down using RNAi resulted in lower ploidy distributions and cells that were incapable of reaching ploidy classes ≥16n. AHR knockdown also resulted in increased DNA synthesis of lower ploidy cells, without impacting apoptosis. Together, these data support a role for AHR in Mk polyploidization and in vivo platelet function, and warrant further detailed investigations. PMID:21226706

The aryl hydrocarbon receptor (AHR) transcription factor regulates megakaryocytic polyploidization.

PubMed

Lindsey, Stephan; Papoutsakis, Eleftherios T

2011-02-01

We propose that the aryl hydrocarbon receptor (AHR) is a novel transcriptional regulator of megakaryopoietic polyploidization. Functional evidence was obtained that AHR impacts in vivo megakaryocytic differentiation and maturation; compared to wild-type mice, AHR-null mice had lower platelet counts, fewer numbers of newly synthesized platelets, increased bleeding times and lower-ploidy megakaryocytes (Mks). AHR mRNA increased 3·6-fold during ex vivo megakaryocytic differentiation, but reduced or remained constant during parallel isogenic granulocytic or erythroid differentiation. We interrogated the role of AHR in megakaryopoiesis using a validated Mk model of megakaryopoiesis, the human megakaryoblastic leukaemia CHRF cell line. Upon CHRF Mk differentiation, AHR mRNA and protein levels increased, AHR protein shifted from the cytoplasm to the nucleus and AHR binding to its consensus DNA binding sequence increased. Protein and mRNA levels of the AHR transcriptional target HES1 also increased. Mk differentiation of CHRF cells where AHR or HES1 was knocked-down using RNAi resulted in lower ploidy distributions and cells that were incapable of reaching ploidy classes ≥16n. AHR knockdown also resulted in increased DNA synthesis of lower ploidy cells, without impacting apoptosis. Together, these data support a role for AHR in Mk polyploidization and in vivo platelet function, and warrant further detailed investigations. © 2011 Blackwell Publishing Ltd.

In vitro re-expression of the aryl hydrocarbon receptor (Ahr) in cultured Ahr-deficient mouse antral follicles partially restores the phenotype to that of cultured wild-type mouse follicles.

PubMed

Ziv-Gal, A; Gao, L; Karman, B N; Flaws, J A

2015-03-01

The aryl hydrocarbon receptor (AHR) mediates the toxic effects of various endocrine disrupting chemicals. In female mice, global deletion of the Ahr (AhrKO) results in slow growth of ovarian antral follicles. No studies, however, have examined whether injection of the Ahr restores the phenotypes of cultured AhrKO ovarian antral follicles to wild-type levels. We developed a system to construct a recombinant adenovirus containing the Ahr to re-express the Ahr in AhrKO granulosa cells and whole antral follicles. We then compared follicle growth and levels of factors in the AHR signaling pathway (Ahr, Ahrr, Cyp1a1, and Cyp1b1) in wild-type, AhrKO, and Ahr re-expressed follicles. Further, we compared the response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in wild-type, AhrKO, and Ahr re-expressed follicles. Ahr injection into AhrKO follicles partially restored their growth pattern to wild-type levels. Further, Ahr re-expressed follicles had significantly higher levels of Ahr, Ahrr, Cyp1a1, and Cyp1b1 compared to wild-type follicles. Upon TCDD treatment, only Cyp1a1 levels were significantly higher in Ahr re-expressed follicles compared to the levels in wild-type follicles. Our system of re-expression of the Ahr partially restores follicle growth and transcript levels of factors in the AHR signaling pathway to wild-type levels. Copyright © 2014 Elsevier Ltd. All rights reserved.

In Vivo Characterization of an AHR-Dependent Long Noncoding RNA Required for Proper Sox9b Expression

PubMed Central

Garcia, Gloria R.; Goodale, Britton C.; Wiley, Michelle W.; La Du, Jane K.; Hendrix, David A.

2017-01-01

Xenobiotic activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prevents the proper formation of craniofacial cartilage and the heart in developing zebrafish. Downstream molecular targets responsible for AHR-dependent adverse effects remain largely unknown; however, in zebrafish sox9b has been identified as one of the most-reduced transcripts in several target organs and is hypothesized to have a causal role in TCDD-induced toxicity. The reduction of sox9b expression in TCDD-exposed zebrafish embryos has been shown to contribute to heart and jaw malformation phenotypes. The mechanisms by which AHR2 (functional ortholog of mammalian AHR) activation leads to reduced sox9b expression levels and subsequent target organ toxicity are unknown. We have identified a novel long noncoding RNA (slincR) that is upregulated by strong AHR ligands and is located adjacent to the sox9b gene. We hypothesize that slincR is regulated by AHR2 and transcriptionally represses sox9b. The slincR transcript functions as an RNA macromolecule, and slincR expression is AHR2 dependent. Antisense knockdown of slincR results in an increase in sox9b expression during both normal development and AHR2 activation, which suggests relief in repression. During development, slincR was expressed in tissues with sox9 essential functions, including the jaw/snout region, otic vesicle, eye, and brain. Reducing the levels of slincR resulted in altered neurologic and/or locomotor behavioral responses. Our results place slincR as an intermediate between AHR2 activation and the reduction of sox9b mRNA in the AHR2 signaling pathway. PMID:28385905

Regulatory effects of dioxin-like and non-dioxin-like PCBs and other AhR ligands on the antioxidant enzymes paraoxonase 1/2/3.

PubMed

Shen, Hua; Robertson, Larry W; Ludewig, Gabriele

2016-02-01

Paraoxonase 1 (PON1), an antioxidant enzyme, is believed to play a critical role in many diseases, including cancer. PCBs are widespread environmental contaminants known to induce oxidative stress and cancer and to produce changes in gene expression of various pro-oxidant and antioxidant enzymes. Thus, it appeared of interest to explore whether PCBs may modulate the activity and/or gene expression of PON1 as well. In this study, we compared the effects of dioxin-like and non-dioxin-like PCBs and of various aryl hydrocarbon receptor (AhR) ligands on PON1 regulation and activity in male and female Sprague-Dawley rats. Our results demonstrate that (i) the non-dioxin-like PCB154, PCB155, and PCB184 significantly reduced liver and serum PON1 activities, but only in male rats; (ii) the non-dioxin-like PCB153, the most abundant PCB in many matrices, did not affect PON1 messenger RNA (mRNA) level in the liver but significantly decreased serum PON1 activity in male rats; (iii) PCB126, an AhR ligand and dioxin-like PCB, increased both PON1 activities and gene expression; and (iv) even though three tested AhR ligands induced CYP1A in several tissues to a similar extent, they displayed differential effects on the three PONs and AhR, i.e., PCB126 was an efficacious inducer of PON1, PON2, PON3, and AhR in the liver, while 3-methylcholantrene induced liver AhR and lung PON3, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent AhR agonist, increased only PON3 in the lung, at the doses and exposure times used in these studies. These results show that PCBs may have an effect on the antioxidant protection by paraoxonases in exposed populations and that regulation of gene expression through AhR is highly diverse.

DDE and PCB 153 independently induce aryl hydrocarbon receptor (AhR) expression in peripheral blood mononuclear cells.

PubMed

Gaspar-Ramírez, Octavio; Pérez-Vázquez, Francisco J; Salgado-Bustamante, Mariana; González-Amaro, Roberto; Hernandez-Castro, Berenice; Pérez-Maldonado, Ivan N

2015-01-01

Recent studies have demonstrated that compounds inducing pro-inflammatory cytokines enhance AhR expression. The aim of this study was 2-fold: (1) to determine if two pro-inflammatory compounds, dichlorodiphenyldichloroethylene (DDE) and 2,2',4,4',5,5'-hexa-chlorobiphenyl (PCB 153), independently affect AhR gene expression in peripheral blood mononuclear cells (PBMC); and (2) if affected, to determine whether the mechanism involved was due to AhR activation or to a pro-inflammatory effect of the chemicals. PBMC isolated from healthy individuals were incubated in the presence of DDE (10 µg/ml) and PCB 153 (20 ng/ml) over time and AhR and CYP1A1 expression was assessed with a real-time PCR technique. The results indicated there was over-expression of the AhR mRNA in PBMC when the cells were treated with DDE and PCB 153. No changes in expression levels of CYP1A1 mRNA were found. Importantly, when the cells were exposed to DDE and PCB 153 in the presence of an antagonist of tumor necrosis factor (TNF)-α, the over-expression of AhR was abolished; as expected, the expression of CYP1A1 was unaffected. In conclusion, these studies demonstrated for the first time an increment of AhR expression "in vitro" in PBMC treated with two pro-inflammatory environmental pollutants, DDE and PCB153. Moreover, the over-expression of AhR was dependent of TNFα induced by DDE and PCB 153 and was independent of AhR activation.

Aryl hydrocarbon receptor (AHR) regulation of L-Type Amino Acid Transporter 1 (LAT-1) expression in MCF-7 and MDA-MB-231 breast cancer cells.

PubMed

Tomblin, Justin K; Arthur, Subha; Primerano, Donald A; Chaudhry, Ateeq R; Fan, Jun; Denvir, James; Salisbury, Travis B

2016-04-15

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is regulated by environmental toxicants that function as AHR agonists such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). L-Type Amino Acid Transporter 1 (LAT1) is a leucine transporter that is overexpressed in cancer. The regulation of LAT1 by AHR in MCF-7 and MDA-MB-231 breast cancer cells (BCCs) was investigated in this report. Ingenuity pathway analysis (IPA) revealed a significant association between TCDD-regulated genes (TRGs) and molecular transport. Overlapping the TCDD-RNA-Seq dataset obtained in this study with a published TCDD-ChIP-seq dataset identified LAT1 as a primary target of AHR-dependent TCDD induction. Short interfering RNA (siRNA)-directed knockdown of AHR confirmed that TCDD-stimulated increases in LAT1 mRNA and protein required AHR expression. TCDD-stimulated increases in LAT1 mRNA were also inhibited by the AHR antagonist CH-223191. Upregulation of LAT1 by TCDD coincided with increases in leucine uptake by MCF-7 cells in response to TCDD. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) assays revealed increases in AHR, AHR nuclear translocator (ARNT) and p300 binding and histone H3 acetylation at an AHR binding site in the LAT1 gene in response to TCDD. In MCF-7 and MDA-MB-231 cells, endogenous levels of LAT1 mRNA and protein were reduced in response to knockdown of AHR expression. Knockdown experiments demonstrated that proliferation of MCF-7 and MDA-MB-231 cells is dependent on both LAT1 and AHR. Collectively, these findings confirm the dependence of cancer cells on leucine uptake and establish a mechanism for extrinsic and intrinsic regulation of LAT1 by AHR. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of human blood levels of two PAH mixtures on the AHR signalling activation pathway and CYP1A1 and COMT target genes in granulosa non-tumor and granulosa tumor cell lines.

PubMed

Zajda, Karolina; Ptak, Anna; Rak, Agnieszka; Fiedor, Elżbieta; Grochowalski, Adam; Milewicz, Tomasz; Gregoraszczuk, Ewa L

2017-08-15

Epidemiological studies have shown a link between problems with offspring of couples living in a contaminated environment in comparison to those who live in an uncontaminated environment. We measured the concentrations of 16 priority polycyclic aromatic hydrocarbons (PAHs) in maternal and cord blood. To explore the mechanism of the effects of PAH mixtures on nonluteinized granulosa cells (HGrC1) and granulosa tumor cells (COV434), as well as cell proliferation and apoptosis, we investigated the effect of PAH mixtures on the expression of the aryl hydrocarbon receptor (AHR), aryl hydrocarbon receptor nuclear translocator (ARNT) and aryl hydrocarbon receptor repressor (AHRR) genes, as well as the expression and activity of target genes cytochrome P450 1A1 (CYP1A1) and catechol-O-methyltransferase (COMT). The cells were exposed to mixture 1 (M1), composed of all 16 priority PAHs, and mixture 2 (M2), composed of five PAHs which are not classified as human carcinogens, and which are observed in the highest amounts both in maternal and cord blood. All 16 priority PAHs were bioavailable in maternal and cord plasma, suggesting that perinatal exposure should be considered. In HGrC1 cells, M1 increased AHR and ARNT, but decreased AHRR expression, in parallel with increased CYP1A1 and COMT expression and activity. M2 decreased AHR and AHRR, and increased ARNT, with no effect on CYP1A1 expression and activity; however, it did increase COMT expression and activity. In tumor cells, M1 lowered AHR and up-regulated AHRR and ARNT expression, consequently decreasing CYP1A1 expression and COMT activity. M2 up-regulated AHR and ARNT, down-regulated AHRR, and had no effect on CYP1A1 and COMT expression, but decreased COMT activity. We hypothesise that, dependent on composition, mixtures of PAHs activate the AHR differently through varying transcription responses: in HGrC1, a canonical AHR mechanism of M1, with activation of CYP1A1 important for detoxication, while in COV434, a

Effect of PCB 126 on aryl hydrocarbon receptor 1 (AHR1) and AHR1 nuclear translocator 1 (ARNT1) mRNA expression and CYP1 monooxygenase activity in chicken (Gallus domesticus) ovarian follicles.

PubMed

Wójcik, Dagmara; Antos, Piotr A; Katarzyńska, Dorota; Hrabia, Anna; Sechman, Andrzej

2015-12-03

The aim of the experiment was to study the in vitro effect of 3,3',4,4',5-pentachlorobiphenyl (PCB 126; a coplanar PCB congener) on aryl hydrocarbon receptor (AHR1) and AHR1 nuclear translocator (ARNT1) mRNA expression and the activity of CYP1 family monooxygenases in chicken ovarian follicles. White (1-4 mm) and yellowish (4-8 mm) prehierarchical follicles as well as fragments of the theca and granulosa layers of the 3 largest preovulatory follicles (F3-F1) were incubated in a medium supplemented with 0 (control group), 1, 10 or 100 nM PCB 126. The incubation was carried out for 6 h or 24 h for determination of mRNA expression of AHR1 and ARNT1 genes (real-time qPCR) and CYP1 monooxygenase activity (EROD and MROD fluorometric assays), respectively. It was found that chicken ovarian follicles express mRNA of AHR1 and ARNT1 genes. A modulatory effect of PCB 126 on AHR1 and ARNT1 expression depended not only on the biphenyl concentration but also on the follicular layer and the maturational state of the follicle. EROD and MROD activities appeared predominantly in the granulosa layer of the yellow preovulatory follicles. PCB 126 induced these activities in a dose-dependent manner in all ovarian follicles. The obtained results suggest that ovarian follicles, especially the granulosa layer, are involved in the detoxification process of PCBs in the laying hen. Taking this finding into consideration it can be suggested that the granulosa layer of the yellow hierarchical follicles plays a key role in the protective mechanism which reduces the amount of transferred dioxin-like compounds into the yolk of the oocyte. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Genetic and epigenetic regulation of AHR gene expression in MCF-7 breast cancer cells: role of the proximal promoter GC-rich region

PubMed Central

Englert, Neal A.; Turesky, Robert J.; Han, Weiguo; Bessette, Erin E.; Spivack, Simon D.; Caggana, Michele; Spink, David C.; Spink, Barbara C.

2014-01-01

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, contributes to carcinogenesis through its role in the regulation of cytochrome P450 1 (CYP1)-catalyzed metabolism of carcinogens. Here, we investigated genetic and epigenetic mechanisms that affect AhR expression. Analyses of the human AHR proximal promoter in MCF-7 human breast cancer cells using luciferase assays and electrophoretic mobility shift assays revealed multiple specificity protein (Sp) 1 binding sequences that are transcriptional activators in vitro. The regulation of AhR expression was evaluated in long-term estrogen exposed (LTEE) MCF-7 cells, which showed increased AhR expression, enhanced CYP1 inducibility, and increased capacity to form DNA adducts when exposed to the dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. The increased AhR expression in LTEE cells was found not to result from increased mRNA stability, differential RNA processing, or decreased DNA methylation. Analysis of the AHR proximal promoter region using chromatin immunoprecipitation confirmed that enhanced expression of AhR in LTEE cells involves changes in histone modifications, notably decreased trimethylation of histone 3, lysine 27. Upon further examination of the GC-rich Sp1-binding region, we confirmed that it contains a polymorphic (GGGGC)n repeat. In a population of newborns from New York State, the allele frequency of (GGGGC)n was n = 4>5≫6, 2. Circular dichroism spectroscopy revealed the ability of sequences of this GC-rich region to form guanine-quadruplex structures in vitro. These studies revealed multiple levels at which AhR expression may be controlled, and offer additional insights into mechanisms regulating AhR expression that can ultimately impact carcinogenesis. PMID:22728919

In Vivo Characterization of an AHR-Dependent Long Noncoding RNA Required for Proper Sox9b Expression.

PubMed

Garcia, Gloria R; Goodale, Britton C; Wiley, Michelle W; La Du, Jane K; Hendrix, David A; Tanguay, Robert L

2017-06-01

Xenobiotic activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) prevents the proper formation of craniofacial cartilage and the heart in developing zebrafish. Downstream molecular targets responsible for AHR-dependent adverse effects remain largely unknown; however, in zebrafish sox9b has been identified as one of the most-reduced transcripts in several target organs and is hypothesized to have a causal role in TCDD-induced toxicity. The reduction of sox9b expression in TCDD-exposed zebrafish embryos has been shown to contribute to heart and jaw malformation phenotypes. The mechanisms by which AHR2 (functional ortholog of mammalian AHR) activation leads to reduced sox9b expression levels and subsequent target organ toxicity are unknown. We have identified a novel long noncoding RNA ( slincR ) that is upregulated by strong AHR ligands and is located adjacent to the sox9b gene. We hypothesize that slincR is regulated by AHR2 and transcriptionally represses sox9b. The slincR transcript functions as an RNA macromolecule, and slincR expression is AHR2 dependent. Antisense knockdown of slincR results in an increase in sox9b expression during both normal development and AHR2 activation, which suggests relief in repression. During development, slincR was expressed in tissues with sox9 essential functions, including the jaw/snout region, otic vesicle, eye, and brain. Reducing the levels of slincR resulted in altered neurologic and/or locomotor behavioral responses. Our results place slincR as an intermediate between AHR2 activation and the reduction of sox9b mRNA in the AHR2 signaling pathway. Copyright © 2017 by The Author(s).

The Nuclear Receptor AhR Controls Bone Homeostasis by Regulating Osteoclast Differentiation via the RANK/c-Fos Signaling Axis.

PubMed

Izawa, Takashi; Arakaki, Rieko; Mori, Hiroki; Tsunematsu, Takaaki; Kudo, Yasusei; Tanaka, Eiji; Ishimaru, Naozumi

2016-12-15

The aryl hydrocarbon receptor (AhR) pathway plays a key role in receptor activator of NF-κB ligand (RANKL)-mediated osteoclastogenesis. However, the mechanism underlying the regulation of AhR expression in osteoclasts and the signaling pathway through which AhR controls osteoclastogenesis remain unclear. We found that the expression of AhR in bone marrow-derived osteoclasts was upregulated by RANKL at an earlier stage than was the expression of signature osteoclast genes such as those encoding cathepsin K and NFAT, cytoplasmic, calcineurin-dependent 1. In response to RANKL, bone marrow macrophages isolated from AhR -/- mice exhibited impaired phosphorylation of Akt and MAPK as well as NF-κB, whereas their response to M-CSF remained unchanged. Osteoclast differentiation mediated by the AhR signaling pathway was also regulated in an RANKL/c-Fos-dependent manner. Furthermore, ligand activation of AhR by the smoke toxin benzo[a]pyrene accelerated osteoclast differentiation in a receptor-dependent manner, and AhR-dependent regulation of mitochondrial biogenesis in osteoclasts was observed. Moreover, AhR -/- mice exhibited impaired bone healing with delayed endochondral ossification. Taken together, the present results suggest that the RANKL/AhR/c-Fos signaling axis plays a critical role in osteoclastogenesis, thereby identifying the potential of AhR in treating pathological, inflammatory, or metabolic disorders of the bone. Copyright © 2016 by The American Association of Immunologists, Inc.

Loss of NR2E3 represses AHR by LSD1 reprogramming, is associated with poor prognosis in liver cancer.

PubMed

Khanal, Tilak; Choi, Kwangmin; Leung, Yuet-Kin; Wang, Jiang; Kim, Dasom; Janakiram, Vinothini; Cho, Sung-Gook; Puga, Alvaro; Ho, Shuk-Mei; Kim, Kyounghyun

2017-09-06

The aryl hydrocarbon receptor (AHR) plays crucial roles in inflammation, metabolic disorder, and cancer. However, the molecular mechanisms regulating AHR expression remain unknown. Here, we found that an orphan nuclear NR2E3 maintains AHR expression, and forms an active transcriptional complex with transcription factor Sp1 and coactivator GRIP1 in MCF-7 human breast and HepG2 liver cancer cell lines. NR2E3 loss promotes the recruitment of LSD1, a histone demethylase of histone 3 lysine 4 di-methylation (H3K4me2), to the AHR gene promoter region, resulting in repression of AHR expression. AHR expression and responsiveness along with H3K4me2 were significantly reduced in the livers of Nr2e3 rd7 (Rd7) mice that express low NR2E3 relative to the livers of wild-type mice. SP2509, an LSD1 inhibitor, fully restored AHR expression and H3K4me2 levels in Rd7 mice. Lastly, we demonstrated that both AHR and NR2E3 are significantly associated with good clinical outcomes in liver cancer. Together, our results reveal a novel link between NR2E3, AHR, and liver cancer via LSD1-mediated H3K4me2 histone modification in liver cancer development.

AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle.

PubMed

Kim, Young-Chae; Seok, Sunmi; Byun, Sangwon; Kong, Bo; Zhang, Yang; Guo, Grace; Xie, Wen; Ma, Jian; Kemper, Byron; Kemper, Jongsook Kim

2018-02-07

Phosphatidylcholines (PC) and S-adenosylmethionine (SAM) are critical determinants of hepatic lipid levels, but how their levels are regulated is unclear. Here, we show that Pemt and Gnmt, key one-carbon cycle genes regulating PC/SAM levels, are downregulated after feeding, leading to decreased PC and increased SAM levels, but these effects are blunted in small heterodimer partner (SHP)-null or FGF15-null mice. Further, aryl hydrocarbon receptor (AhR) is translocated into the nucleus by insulin/PKB signaling in the early fed state and induces Pemt and Gnmt expression. This induction is blocked by FGF15 signaling-activated SHP in the late fed state. Adenoviral-mediated expression of AhR in obese mice increases PC levels and exacerbates steatosis, effects that are blunted by SHP co-expression or Pemt downregulation. PEMT, AHR, and PC levels are elevated in simple steatosis patients, but PC levels are robustly reduced in steatohepatitis-fibrosis patients. This study identifies AhR and SHP as new physiological regulators of PC/SAM levels.

Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR

PubMed Central

Sahm, Felix; Rauschenbach, Katharina J.; Trump, Saskia; Winter, Marcus; Ott, Martina; Ochs, Katharina; Lutz, Christian; Liu, Xiangdong; Anastasov, Natasa; Lehmann, Irina; Höfer, Thomas; von Deimling, Andreas; Wick, Wolfgang; Platten, Michael

2014-01-01

Indoleamine-2,3-dioxygenase (IDO) inhibitors have entered clinical trials based on their ability to restore anti-tumor immunity in preclinical studies. However, the mechanisms leading to constitutive expression of IDO in human tumors are largely unknown. Here we analyzed the pathways mediating constitutive IDO expression in human cancer. IDO-positive tumor cells and tissues showed basal phosphorylation and acetylation of STAT3 as evidenced by western blotting and immunoprecipitation. Inhibition of IL-6 or STAT3 using siRNA and/or pharmacological inhibitors reduced IDO mRNA and protein expression as well as kynurenine formation. In turn, IDO enzymatic activity activated the AHR as shown by the induction of AHR target genes. IDO-mediated AHR activation induced IL-6 expression, while inhibition or knockdown of the AHR reduced IL-6 expression. IDO activity thus sustains its own expression via an autocrine AHR–IL-6–STAT3 signaling loop. Inhibition of the AHR–IL-6–STAT3 signaling loop restored T-cell proliferation in mixed leukocyte reactions performed in the presence of IDO-expressing human cancer cells. Identification of the IDO-AHR-IL-6-STAT3 signaling loop maintaining IDO expression in human cancers reveals novel therapeutic targets for the inhibition of this core pathway promoting immunosuppression of human cancers. The relevance of the IDO-AHR-IL-6-STAT3 transcriptional circuit is underscored by the finding that high expression of its members IDO, STAT3 and the AHR target gene CYP1B1 is associated with reduced relapse-free survival in lung cancer patients. PMID:24657910

Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans.

PubMed

Smith, Susan H; Jayawickreme, Channa; Rickard, David J; Nicodeme, Edwige; Bui, Thi; Simmons, Cathy; Coquery, Christine M; Neil, Jessica; Pryor, William M; Mayhew, David; Rajpal, Deepak K; Creech, Katrina; Furst, Sylvia; Lee, James; Wu, Dalei; Rastinejad, Fraydoon; Willson, Timothy M; Viviani, Fabrice; Morris, David C; Moore, John T; Cote-Sierra, Javier

2017-10-01

Tapinarof (GSK2894512) is a naturally derived topical treatment with demonstrated efficacy for patients with psoriasis and atopic dermatitis, although the biologic target and mechanism of action had been unknown. We demonstrate that the anti-inflammatory properties of tapinarof are mediated through activation of the aryl hydrocarbon receptor (AhR). We show that tapinarof binds and activates AhR in multiple cell types, including cells of the target tissue-human skin. In addition, tapinarof moderates proinflammatory cytokine expression in stimulated peripheral blood CD4+ T cells and ex vivo human skin, and impacts barrier gene expression in primary human keratinocytes; both of these processes are likely to be downstream of AhR activation based on current evidence. That the anti-inflammatory properties of tapinarof derive from AhR agonism is conclusively demonstrated using the mouse model of imiquimod-induced psoriasiform skin lesions. Topical treatment of AhR-sufficient mice with tapinarof leads to compound-driven reductions in erythema, epidermal thickening, and tissue cytokine levels. In contrast, tapinarof has no impact on imiquimod-induced skin inflammation in AhR-deficient mice. In summary, these studies identify tapinarof as an AhR agonist and confirm that its efficacy is dependent on AhR. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Potential involvement of placental AhR in unexplained recurrent spontaneous abortion.

PubMed

Wu, Y; Chen, X; Chang, X; Huang, Y J; Bao, S; He, Q; Li, Y; Zheng, J; Duan, T; Wang, K

2016-01-01

Recurrent spontaneous abortion (RSA) is a common complication of pregnancy. Recent studies have demonstrated that the aryl hydrocarbon receptor (AhR) might play important roles in establishing and maintaining early pregnancy. In this study, we found that placental AhR protein levels were significantly lower and placental CYP1A1 mRNA levels were higher in unexplained RSA (URSA) patients than in control subjects. The results of immunohistochemical analyzes showed that placental AhR was expressed in syncytiotrophoblast cells and that the level of AhR was markedly lower in these cells in URSA subjects than in control subjects. β-Naphthoflavone (β-NF, an AhR ligand) at 5μM significantly inhibited proliferation and migration in HTR-8/SVneo cells and was associated with the activation of AhR. Moreover, overexpressing AhR in JAR cells significantly increased CYP1A1 mRNA levels and inhibited cell migration. These results indicate that AhR is highly activated in URSA placentas and that the activation of AhR in the placenta might impair trophoblast cell proliferation and migration, possibly leading to the occurrence of URSA. Copyright © 2015 Elsevier Inc. All rights reserved.

Benzo[ghi]perylene activates the AHR pathway to exert biological effects on the NL-20 human bronchial cell line.

PubMed

Zaragoza-Ojeda, Montserrat; Eguía-Aguilar, Pilar; Perezpeña-Díazconti, Mario; Arenas-Huertero, Francisco

2016-08-10

Polycyclic aromatic hydrocarbons (PAH) are produced by incomplete combustion of organic material. In the Mexico City atmosphere, the most abundant PAH is benzo[ghi]perylene (BghiP), a gasoline combustion marker. At present, there are no reports of the effects of BghiP on human bronchial cells, so the aim of the study was to evaluate the effects in vitro of BghiP on the NL-20 cell line. Results showed that BghiP induced the formation of small vesicles throughout the cytoplasm, with absence of nuclear fragmentation. At 48h exposition, damage in cell membrane increased significantly at 1.24μg/mL of BghiP (p<0.05). Immunocytochemistry revealed that BghiP provokes nuclear translocation of AhR receptor, which indicates that this compound can induce transcription of genes via receptor binding (AhR pathway activation). BghiP induced a two-fold increase (p<0.05) in the expression of AhR and CYP4B1 (a lung-specific pathway effector). In the presence of the receptor antagonist CH-223191, the loss of viability, the nuclear translocation and the overexpression of genes decreased, though this did not prevent the formation of vesicles. BghiP induced oxidative stress and in presence of the receptor antagonist this increased significantly. In conclusion, BghiP can activate the overexpression of AhR and CYP4B1, and the effects are abated by the AhR receptor antagonist. This is the first report to prove that BghiP utilizes the AhR pathway to exert its toxic effects on the NL-20 human bronchial cell line . Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Parametric and cycle tests of a 40-A-hr bipolar nickel-hydrogen battery

NASA Technical Reports Server (NTRS)

Cataldo, R. L.

1986-01-01

A series of tests was performed to characterize battery performance relating to certain operating parameters which included charge current, discharge current, temperature and pressure. The parameters were varied to confirm battery design concepts and to determine optimal operating conditions. Spacecraft power requirements are constantly increasing. Special spacecraft such as the Space Station and platforms will require energy storage systems of 130 and 25 kWh, respectively. The complexity of these high power systems will demand high reliability, and reduced mass and volume. A system that uses batteries for storage will require a cell count in excess of 400 units. These cell units must then be assembled into several batteries with over 100 cells in a series connected string. In an attempt to simplify the construction of conventional cells and batteries, the NASA Lewis Research Center battery systems group initiated work on a nickel-hydrogen battery in a bipolar configuration in early 1981. Features of the battery with this bipolar construction show promise in improving both volumetric and gravimetric energy densities as well as thermal management. Bipolar construction allows cooling in closer proximity to the cell components, thus heat removal can be accomplished at a higher rejection temperature than conventional cell designs. Also, higher current densities are achievable because of low cell impedance. Lower cell impedance is achieved via current flow perpendicular to the electrode face, thus reducing voltage drops in the electrode grid and electrode terminals tabs.

The Nuclear Receptor AhR Controls Bone Homeostasis by Regulating Osteoclast Differentiation via the RANK/c-Fos Signaling Axis

PubMed Central

Izawa, Takashi; Arakaki, Rieko; Mori, Hiroki; Tsunematsu, Takaaki; Kudo, Yasusei; Tanaka, Eiji

2016-01-01

The aryl hydrocarbon receptor (AhR) pathway plays a key role in receptor activator of NF-κB ligand (RANKL)–mediated osteoclastogenesis. However, the mechanism underlying the regulation of AhR expression in osteoclasts and the signaling pathway through which AhR controls osteoclastogenesis remain unclear. We found that the expression of AhR in bone marrow–derived osteoclasts was upregulated by RANKL at an earlier stage than was the expression of signature osteoclast genes such as those encoding cathepsin K and NFAT, cytoplasmic, calcineurin-dependent 1. In response to RANKL, bone marrow macrophages isolated from AhR−/− mice exhibited impaired phosphorylation of Akt and MAPK as well as NF-κB, whereas their response to M-CSF remained unchanged. Osteoclast differentiation mediated by the AhR signaling pathway was also regulated in an RANKL/c-Fos–dependent manner. Furthermore, ligand activation of AhR by the smoke toxin benzo[a]pyrene accelerated osteoclast differentiation in a receptor-dependent manner, and AhR-dependent regulation of mitochondrial biogenesis in osteoclasts was observed. Moreover, AhR−/− mice exhibited impaired bone healing with delayed endochondral ossification. Taken together, the present results suggest that the RANKL/AhR/c-Fos signaling axis plays a critical role in osteoclastogenesis, thereby identifying the potential of AhR in treating pathological, inflammatory, or metabolic disorders of the bone. PMID:27849171

Report on Lithium Ion Battery Trade Studies to Support the Exploration Technology Development Program (ETDP) Energy Storage Project

NASA Technical Reports Server (NTRS)

Green, Robert D.; Kissock, Barbara I.; Bennett, William R.

2010-01-01

This report documents the results of two system related analyses to support the Exploration Technology Development Program (ETDP) Energy Storage Project. The first study documents a trade study to determine the optimum Li-ion battery cell capacity for the ascent stage battery for the Altair lunar lander being developed under the Constellation Systems program. The battery cell capacity for the Ultra High Energy (UHE) Li-ion battery initially chosen as the target for development was 35 A-hr; this study concludes that a 19.4 A-hr cell capacity would be more optimum from a minimum battery mass perspective. The second study in this report is an assessment of available low temperature Li-ion battery cell performance data to determine whether lowering the operating temperature range of the Li-ion battery, in a rover application, could save overall system mass by eliminating thermal control system mass normally needed to maintain battery temperature within a tighter temperature limit than electronics or other less temperature sensitive components. The preliminary assessment for this second study indicates that the reduction in the thermal control system mass is negated by an increase in battery mass to compensate for the loss in battery capacity due to lower temperature operating conditions.

Phytomonitoring and phytoremediation of agrochemicals and related compounds based on recombinant cytochrome P450s and aryl hydrocarbon receptors (AhRs).

PubMed

Shimazu, Sayuri; Inui, Hideyuki; Ohkawa, Hideo

2011-04-13

Molecular mechanisms of metabolism and modes of actions of agrochemicals and related compounds are important for understanding selective toxicity, biodegradability, and monitoring of biological effects on nontarget organisms. It is well-known that in mammals, cytochrome P450 (P450 or CYP) monooxygenases metabolize lipophilic foreign compounds. These P450 species are inducible, and both CYP1A1 and CYP1A2 are induced by aryl hydrocarbon receptor (AhR) combined with a ligand. Gene engineering of P450 and NADPH cytochrome P450 oxidoreductase (P450 reductase) was established for bioconversion. Also, gene modification of AhRs was developed for recombinant AhR-mediated β-glucronidase (GUS) reporter assay of AhR ligands. Recombinant P450 genes were transformed into plants for phytoremediation, and recombinant AhR-mediated GUS reporter gene expression systems were each transformed into plants for phytomonitoring. Transgenic rice plants carrying CYP2B6 metabolized the herbicide metolachlor and remarkably reduced the residues in the plants and soils under paddy field conditions. Transgenic Arabidopsis plants carrying recombinant guinea pig (g) AhR-mediated GUS reporter genes detected PCB126 at the level of 10 ng/g soils in the presence of biosurfactants MEL-B. Both phytomonitoring and phytoremediation plants were each evaluated from the standpoint of practical uses.

The anticonvulsant action of AHR-11748 on kindled amygdaloid seizures in rats.

PubMed

Albertson, T E; Walby, W F

1987-03-01

The anticonvulsant effectiveness of AHR-11748 (3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide) was evaluated in the kindled amygdaloid seizure model in rats. Doses of AHR-11748 that did not cause prestimulation toxicity significantly attenuated elicited afterdischarge durations and the severity of the accompanying behavioral convulsive response in previously kindled rats. AHR-11748 (25-100 mg/kg i.p.) was evaluated at 30 min in previously kindled rats using both threshold (20 microA increments) and suprathreshold (400 microA) paradigms. AHR-11748 (50-100.mg/kg) reduced suprathreshold elicited after discharges and seizure severity. Utilizing a suprathreshold kindling paradigm, the maximum anticonvulsant effectiveness for the 100 mg/kg i.p. dose of AHR-11748 was seen at 180 min. AHR-11748 significantly elevated seizure thresholds only at the 100 mg/kg dose. AHR-11748 (25-100 mg/kg) significantly reduced the severity of threshold elicited seizures. When AHR-11748 (50 and 100 mg/kg i.p.) was administered daily during kindling acquisition, the number of daily trials necessary to complete kindling significantly increased. A reduction in both the duration and the severity of the responses induced by the daily stimulations during the acquisition period was seen with AHR-11748 treatment. This study has demonstrated that AHR-11748 significantly modifies both the acquisition of kindling and the fully kindled amygdaloid seizures at doses that do not cause behavioral toxicity.

The regulation mechanisms of AhR by molecular chaperone complex.

PubMed

Kudo, Ikuru; Hosaka, Miki; Haga, Asami; Tsuji, Noriko; Nagata, Yuhtaroh; Okada, Hirotaka; Fukuda, Kana; Kakizaki, Yuka; Okamoto, Tomoya; Grave, Ewa; Itoh, Hideaki

2018-03-01

The AhR, so called the dioxin receptor, is a member of the nuclear receptor superfamily. The ligand-free AhR forms a cytosolic protein complex with the molecular chaperone HSP90, co-chaperone p23, and XAP2 in the cytoplasm. Following ligand binding like 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), the AhR translocates into the nucleus. Although it has been reported that HSP90 regulates the translocation of the AhR to the nucleus, the precise activation mechanisms of the AhR have not yet been fully understood. AhR consists of the N-terminal bHLH domain containing NLS and NES, the middle PAS domain and the C-terminal transactivation domain. The PAS domain is familiar as a ligand and HSP90 binding domain. In this study, we focused on the bHLH domain that was thought to be a HSP90 binding domain. We investigated the binding properties of bHLH to HSP90. We analyzed the direct interaction of bHLH with HSP90, p23 and XAP2 using purified proteins. We found that not only the PAS domain but also the bHLH domain bound to HSP90. The bHLH domain forms complex with HSP90, p23 and XAP2. We also determined the bHLH binding domain was HSP90 N-domain. The bHLH domain makes a complex with HSP90, p23 and XAP2 via the HSP90 N-domain. Although the NLS is closed in the absence of a ligand, the structure of AhR will be changed in the presence of a ligand, which leads to NLS open, result in the nuclear translocation of AhR.

AHR/CYP1A1 interplay triggers lymphatic barrier breaching in breast cancer spheroids by inducing 12(S)-HETE synthesis.

PubMed

Nguyen, Chi Huu; Brenner, Stefan; Huttary, Nicole; Atanasov, Atanas Georgiev; Dirsch, Verena Maria; Chatuphonprasert, Waranya; Holzner, Sivio; Stadler, Serena; Riha, Juliane; Krieger, Sigurd; de Martin, Rainer; Bago-Horvath, Zsuzsanna; Krupitza, Georg; Jäger, Walter

2016-11-15

A causal link between overexpression of aryl hydrocarbon receptor (AHR) and its target cytochrome P450 1A1 (CYP1A1) and metastatic outgrowth of various cancer entities has been established. Nevertheless, the mechanism how AHR/CYP1A1 support metastasis formation is still little understood. In vitro we discovered a potential mechanism facilitating tumour dissemination based on the production of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). Utilising a three-dimensional lymph endothelial cell (LEC) monolayer & MDA-MB231 breast cancer cell spheroid co-culture model in combination with knock-down approach allowed elucidation of the molecular/biochemical basis of AHR/CYP1A1-induced tumour breaching through the LEC barrier. Enzyme immunoassay evidenced the potential of recombinant CYP1A1 to synthesise 12(S)-HETE in vitro and qPCR and Western blotting measured gene and protein expression in specific experimental settings. In detail, AHR induced CYP1A1 expression and 12(S)-HETE secretion in tumour spheroids, which caused LEC junction retraction thereby forming large discontinuities allowing transmigration of the tumour. This was enforced by the activating AHR ligand 6-formylindolo (3,3-b)carbazole (FICZ), or inhibited by the AHR antagonist 3,3’-diindolylmethane (DIM) as well as by siRNA against AHR and CYP1A1. AHR and NF-κB were negatively cross talking and therefore, the inhibition of AHR (but not CYP1A1) induced RELA, RELB, NFKB1, NFKB2 and the NF-κB target MMP1, which itself promotes tumour intravasation by a mechanism that is different from 12(S)-HETE. Conversely, the inhibition of NFKB2 induced AHR, CYP1A1 and 12(S)-HETE synthesis. The approved clinical drugs guanfacine and vinpocetine, which inhibit CYP1A1 and NF-κB, respectively, significantly inhibited LEC barrier breaching in vitro indicating an option to reduce metastatic dissemination.

TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

EPA Science Inventory

Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...

AHR prevents human IL-1R1hi ILC3 differentiation to natural killer cells

PubMed Central

Hughes, Tiffany; Briercheck, Edward L.; Freud, Aharon G.; Trotta, Rossana; McClory, Susan; Scoville, Steven D.; Keller, Karen; Deng, Youcai; Cole, Jordan; Harrison, Nicholas; Mao, Charlene; Zhang, Jianying; Benson, Don M.; Yu, Jianhua; Caligiuri, Michael A.

2014-01-01

SUMMARY Accumulating evidence indicates that human natural killer (NK) cells develop in secondary lymphoid tissue (SLT) through a so-called “stage 3” developmental intermediate minimally characterized by a CD34-CD117+CD94- immunophenotype that lacks mature NK cell function. This stage 3 population is heterogeneous, potentially composed of functionally distinct innate lymphoid cell (ILC) types that includes interleukin-1 receptor (IL-1R1) positive, IL-22-producing ILC3s. Whether human ILC3s are developmentally related to NK cells is a subject of ongoing investigation. Here we show that antagonism of the aryl hydrocarbon receptor (AHR) or silencing of AHR gene expression promotes differentiation of tonsillar IL-22-producing IL-1R1hi human ILC3s to CD56brightCD94+ IFN-gamma-producing cytolytic mature NK cells expressing eomesodermin (EOMES) and T-Box Protein 21 (TBX21 or TBET). Hence, AHR is a transcription factor that prevents human IL-1R1hi ILC3s from differentiating into NK cells. PMID:24953655

Aryl Hydrocarbon Receptor (AhR) Deletion in Cerebellar Granule Neuron Precursors Impairs Neurogenesis

PubMed Central

Dever, Daniel P.; Adham, Zachariah O.; Thompson, Bryan; Genestine, Matthieu; Cherry, Jonathan; Olschowka, John A.; DiCicco-Bloom, Emanuel; Opanashuk, Lisa A.

2015-01-01

The aryl hydrocarbon receptor (AhR) is a ligand-activated member of the basic-helix-loop-helix (bHLH)/PER-ARNT-SIM(PAS) transcription factor superfamily that also mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence suggests that AhR influences the development of many tissues, including the central nervous system. Our previous studies suggest that sustained AhR activation by TCDD and/or AhR deletion disrupts cerebellar granule neuron precursor (GNP) development. In the current study, to determine whether endogenous AhR controls GNP development in a cell autonomous manner, we created a GNP-specific AhR deletion mouse, AhRfx/fx/Math1CRE/+ (AhR CKO). Selective AhR deletion in GNPs produced abnormalities in proliferation and differentiation. Specifically, fewer GNPs were engaged in S-phase, as demonstrated by ~25% reductions in thymidine (in vitro) and BrdU (in vivo) incorporation. Furthermore, total granule neuron numbers in the IGL at PND21 and PND60 were diminished in AhR CKO mice compared to controls. On the other hand, differentiation was enhanced, including ~40% increase in neurite outgrowth and 50% increase in GABARα6 receptor expression in deletion mutants. Our results suggest that AhR activity plays a role in regulating granule neuron number and differentiation, possibly by coordinating this GNP developmental transition. These studies provide novel insights for understanding the normal roles of AhR signaling during cerebellar granule cell neurogenesis, and may have important implications for the effects of environmental factors in cerebellar dysgenesis. PMID:26243376

UAV State Estimation Modeling Techniques in AHRS

NASA Astrophysics Data System (ADS)

Razali, Shikin; Zhahir, Amzari

2017-11-01

Autonomous unmanned aerial vehicle (UAV) system is depending on state estimation feedback to control flight operation. Estimation on the correct state improves navigation accuracy and achieves flight mission safely. One of the sensors configuration used in UAV state is Attitude Heading and Reference System (AHRS) with application of Extended Kalman Filter (EKF) or feedback controller. The results of these two different techniques in estimating UAV states in AHRS configuration are displayed through position and attitude graphs.

TCDD and omeprazole prime platelets through the aryl hydrocarbon receptor (AhR) non-genomic pathway.

PubMed

Pombo, Mónica; Lamé, Michael W; Walker, Naomi J; Huynh, Danh H; Tablin, Fern

2015-05-19

The role of the aryl hydrocarbon receptor (AhR) in hemostasis has recently gained increased attention. Here, we demonstrate, by qRT-PCR and western blot, that human platelets express both AhR mRNA and AhR protein. AhR protein levels increase in a dose dependent manner when incubated with either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or omeprazole. Treatment of platelets with puromycin blocks increased AhR protein synthesis in the presence of AhR activators. Additionally, treatment of platelets with either activator results in phosphorylation of p38MAPK and cPLA2, two key signaling molecules in platelet activation pathways. Using the AhR competitive inhibitors alpha naphthoflavone and CH-223191, we show that phosphorylation of p38MAPK is AhR dependent. Further, inhibition of p38MAPK blocks downstream cPLA2 phosphorylation induced by TCDD or omeprazole. Treatment with AhR activators results in platelet priming, as demonstrated by increased platelet aggregation, which is inhibited by AhR antagonists. Our data support a model of the platelet AhR non-genomic pathway in which treatment with AhR activators results in increased expression of the AhR, phosphorylation of p38MAPK and cPLA2, leading to platelet priming in response to agonist. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Comparison of hepatic NRF2 and AHR binding in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treated mice demonstrates NRF2-independent PKM2 induction.

PubMed

Nault, Rance; Doskey, Claire M; Fader, Kelly A; Rockwell, Cheryl E; Zacharewski, Timothy R

2018-05-11

2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) induces hepatic oxidative stress following activation of the aryl hydrocarbon receptor (AhR). Our recent studies showed TCDD induced pyruvate kinase muscle isoform 2 ( Pkm2 ) as a novel antioxidant response in normal differentiated hepatocytes. To investigate cooperative regulation between nuclear factor, erythroid derived 2, like 2 ( Nrf2 ) and the AhR in the induction of Pkm2 , hepatic ChIP-seq analyses were integrated with RNA-seq time course data from mice treated with TCDD for 2 - 168h. ChIP-seq analysis 2h after TCDD treatment identified genome-wide NRF2 enrichment. Approximately 842 NRF2 enriched regions were located in the regulatory region of differentially expressed genes (DEGs) while 579 DEGs showed both NRF2 and AhR enrichment. Sequence analysis of regions with overlapping NRF2 and AhR enrichment showed over-representation of either antioxidant or dioxin response elements (ARE and DRE, respectively), although 18 possessed both motifs. NRF2 exhibited negligible enrichment within a closed Pkm chromatin region while the AhR was enriched 29-fold. Furthermore, TCDD induced Pkm2 in primary hepatocytes from wild-type and Nrf2 null mice, indicating NRF2 is not required. Although NRF2 and AhR cooperate to regulate numerous antioxidant gene expression responses, the induction of Pkm2 by TCDD is independent of ROS-mediated NRF2 activation. The American Society for Pharmacology and Experimental Therapeutics.

The Aryl Hydrocarbon Receptor (AhR) as a Drug Target for Cancer Chemotherapy.

PubMed

Safe, Stephen; Cheng, Yating; Jin, Un-Ho

2017-02-01

The aryl hydrocarbon receptor (AhR) is overexpressed in some patients with different tumor types, and the receptor can be a negative or positive prognostic factor. There is also evidence from both in vivo and in vitro cell culture models that the AhR can exhibit tumor-specific pro-oncogenic and tumor suppressor-like functions and therefore can be treated with AhR antagonists or agonists, respectively. Successful clinical applications of AhR ligands will require the synthesis and development of selective AhR modulators (SAhRMs) with tumor-specific AhR agonist or antagonist activity, and some currently available compounds such as indole-3-carbinol and diindolylmethane-(DIM) and synthetic AhR antagonists are potential drug candidates. There is also evidence that some AhR-active pharmaceuticals, including tranilast, flutamide, hydroxytamoxifen and omeprazole or their derivatives, may be effective AhR-dependent anticancer agents for single or combination cancer chemotherapies for treatment of breast and pancreatic cancers.

Teratogenic impact of dioxin-activated AHR in laboratory animals

EPA Science Inventory

AHR and ARNT are expressed in mouse and human palatal shelves and in the urinary tract of the mouse fetus. AHR expression, translocation to the nucleus, binding to DRE, and activation are required for mediation of TCDD-induction of CP and HN. Although the human palate requires a ...

EGCG protects endothelial cells against PCB 126-induced inflammation through inhibition of AhR and induction of Nrf2-regulated genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, Sung Gu; Department of Animal and Food Sciences, College of Agriculture, University of Kentucky, Lexington, KY 40536; Han, Seong-Su

Tea flavonoids such as epigallocatechin gallate (EGCG) protect against vascular diseases such as atherosclerosis via their antioxidant and anti-inflammatory functions. Persistent and widespread environmental pollutants, including polychlorinated biphenyls (PCB), can induce oxidative stress and inflammation in vascular endothelial cells. Even though PCBs are no longer produced, they are still detected in human blood and tissues and thus considered a risk for vascular dysfunction. We hypothesized that EGCG can protect endothelial cells against PCB-induced cell damage via its antioxidant and anti-inflammatory properties. To test this hypothesis, primary vascular endothelial cells were pretreated with EGCG, followed by exposure to the coplanar PCBmore » 126. Exposure to PCB 126 significantly increased cytochrome P450 1A1 (Cyp1A1) mRNA and protein expression and superoxide production, events which were significantly attenuated following pretreatment with EGCG. Similarly, EGCG also reduced DNA binding of NF-κB and downstream expression of inflammatory markers such as monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion protein-1 (VCAM-1) after PCB exposure. Furthermore, EGCG decreased endogenous or base-line levels of Cyp1A1, MCP-1 and VCAM-1 in endothelial cells. Most of all, treatment of EGCG upregulated expression of NF-E2-related factor 2 (Nrf2)-controlled antioxidant genes, including glutathione S transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1), in a dose-dependent manner. In contrast, silencing of Nrf2 increased Cyp1A1, MCP-1 and VCAM-1 and decreased GST and NQO1 expression, respectively. These data suggest that EGCG can inhibit AhR regulated genes and induce Nrf2-regulated antioxidant enzymes, thus providing protection against PCB-induced inflammatory responses in endothelial cells. -- Highlights: ► PCBs cause endothelial inflammation and subsequent atherosclerosis. ► Nutrition can modulate toxicity by environmental pollutants. �

Cigarette smoke-induced cell cycle arrest in spermatocytes [GC-2spd(ts)] is mediated through crosstalk between Ahr-Nrf2 pathway and MAPK signaling.

PubMed

Esakky, Prabagaran; Hansen, Deborah A; Drury, Andrea M; Moley, Kelle H

2015-02-01

Our earlier studies have demonstrated that the cigarette smoke in the form of cigarette smoke condensate (CSC) causes growth arrest of a mouse spermatocyte cell line [GC-2spd(ts)] through activation of the AHR-NRF2 pathway. The present study demonstrates the CSC-activated p38 and ERK MAPK signaling in GC-2spd(ts) via arylhydrocarbon receptor (AHR). Pharmacological inhibition by using AHR-antagonist, or p38 MAPK and ERK (MEK1) inhibitors significantly abrogates CSC-induced growth arrest by AHR and MAPK inactivation. QRT-PCR, western blot, and immunofluorescence of Ahr-target of Nrf2, and stress-inducible growth suppressive Atf3 and E2f4 following treatments indicate a crosstalk among these pathways. Regulation of Atf3 by Nrf2 and Ahr through RNA interference suggests the existence of a cross-regulatory loop between the targets. CSC induction of E2f4 via Atf3 and its regulation by pharmacological inhibitors reveal a possible regulatory mechanism of growth inhibitory CSC. SiRNA silencing of Ahr, Nrf2, Atf3, and E2f4 genes and downregulation of cyclins by CSC corroborate the growth inhibitory effect of cigarette smoke. Thus, the data obtained suggest that the CSC-mediated MAPKs and AHR-NRF2 crosstalks lay the molecular basis for the growth arrest and cell death of spermatocytes. © The Author (2014). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

Cellular responses to oxidative stress: the [Ah] gene battery as a paradigm.

PubMed Central

Nebert, D W; Petersen, D D; Fornace, A J

1990-01-01

A major source of oxidative stress in animals is plant stress metabolites, also termed phytoalexins. The aromatic hydrocarbon-responsive [Ah] gene battery is considered here as a model system in which we can study metabolically coordinated enzymes that respond to phytoalexin-induced oxidative stress. In the mouse, the [Ah] battery comprises at least six genes: two Phase I genes, CYP1A1 and CYP1A2; and four Phase II genes, Nmo-1, Aldh-1, Ugt-1, and Gt-1. All six genes appear to be regulated positively by inducers such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other ligands of the Ah receptor. In the absence of foreign inducer, the control of Nmo-1 gene expression is independent of the control of CYP1A1 and CYP1A2 gene expression. The radiation deletion homozygote c14CoS/c14CoS mouse is lacking about 1.1 centiMorgans of chromosome 7. Although having no detectable CYP1A1 or CYP1A2 activation, the untreated c14CoS/c14CoS mouse exhibits markedly elevated transcripts of the Nmo-1 gene and three growth arrest- and DNA damage-inducible (gadd) genes. These data suggest that the missing region on chromosome 7 in the c14CoS/c14CoS mouse contains a gene(s), which we propose to call Nmo-1n, encoding a trans-acting factor(s) that is a negative effector of the Nmo-1 and gadd genes. The three other [Ah] battery Phase II genes behave similarly to Nmo-1 in the c14CoS/c14CoS mouse. This coordinated response to oxidative stress and DNA damage, by way of the release of a mammalian battery of genes from negative control, bears an interesting resemblance to the SOS response in bacteria. PMID:2272308

Screening a mouse liver gene expression Compendium Identifies Effectors of the Aryl Hydrocarbon receptor (AhR)

EPA Science Inventory

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the biological and toxic effects of 2,3, 7 ,8-tetrachlorodibenzo-p-dioxin {TCDD), dioxin-like compounds (DLC) as well as some drugs and endogenous tryptophan metabolites. Short-term act...

AhR-mediated gene expression in the developing mouse telencephalon.

PubMed

Gohlke, Julia M; Stockton, Pat S; Sieber, Stella; Foley, Julie; Portier, Christopher J

2009-11-01

We hypothesize that TCDD-induced developmental neurotoxicity is modulated through an AhR-dependent interaction with key regulatory neuronal differentiation pathways during telencephalon development. To test this hypothesis we examined global gene expression in both dorsal and ventral telencephalon tissues in E13.5 AhR-/- and wildtype mice exposed to TCDD or vehicle. Consistent with previous biochemical, pathological and behavioral studies, our results suggest TCDD initiated changes in gene expression in the developing telencephalon are primarily AhR-dependent, as no statistically significant gene expression changes are evident after TCDD exposure in AhR-/- mice. Based on a gene regulatory network for neuronal specification in the developing telencephalon, the present analysis suggests differentiation of GABAergic neurons in the ventral telencephalon is compromised in TCDD exposed and AhR-/- mice. In addition, our analysis suggests Sox11 may be directly regulated by AhR based on gene expression and comparative genomics analyses. In conclusion, this analysis supports the hypothesis that AhR has a specific role in the normal development of the telencephalon and provides a mechanistic framework for neurodevelopmental toxicity of chemicals that perturb AhR signaling.

Aryl hydrocarbon receptor (AHR): "pioneer member" of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of "sensors" of foreign and endogenous signals.

PubMed

Nebert, Daniel W

2017-07-01

The basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family comprises many transcription factors, found throughout all three kingdoms of life; bHLH/PAS members "sense" innumerable intracellular and extracellular "signals" - including endogenous compounds, foreign chemicals, gas molecules, redox potential, photons (light), gravity, heat, and osmotic pressure. These signals then initiate downstream signaling pathways involved in responding to that signal. The term "PAS", abbreviation for "per-Arnt-sim" was first coined in 1991. Although the mouse Arnt gene was not identified until 1991, evidence of its co-transcriptional binding partner, aryl hydrocarbon receptor (AHR), was first reported in 1974 as a "sensor" of foreign chemicals, up-regulating cytochrome P450 family 1 (CYP1) and other enzyme activities that usually metabolize the signaling chemical. Within a few years, AHR was proposed also to participate in inflammation. The mouse [Ah] locus was shown (1973-1989) to be relevant to chemical carcinogenesis, mutagenesis, toxicity and teratogenesis, the mouse Ahr gene was cloned in 1992, and the first Ahr(-/-) knockout mouse line was reported in 1995. After thousands of studies from the early 1970s to present day, we now realize that AHR participates in dozens of signaling pathways involved in critical-life processes, affecting virtually every organ and cell-type in the animal, including many invertebrates. Copyright © 2017 Elsevier Ltd. All rights reserved.

Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR).

PubMed

Seok, Seung-Hyeon; Ma, Zhi-Xiong; Feltenberger, John B; Chen, Hongbo; Chen, Hui; Scarlett, Cameron; Lin, Ziqing; Satyshur, Kenneth A; Cortopassi, Marissa; Jefcoate, Colin R; Ge, Ying; Tang, Weiping; Bradfield, Christopher A; Xing, Yongna

2018-02-09

Cellular metabolites act as important signaling cues, but are subject to complex unknown chemistry. Kynurenine is a tryptophan metabolite that plays a crucial role in cancer and the immune system. Despite its atypical, non-ligand-like, highly polar structure, kynurenine activates the aryl hydrocarbon receptor (AHR), a PER, ARNT, SIM (PAS) family transcription factor that responds to diverse environmental and cellular ligands. The activity of kynurenine is increased 100-1000-fold by incubation or long-term storage and relies on the hydrophobic ligand-binding pocket of AHR, with identical structural signatures for AHR induction before and after activation. We purified trace-active derivatives of kynurenine and identified two novel, closely related condensation products, named trace-extended aromatic condensation products (TEACOPs), which are active at low picomolar levels. The synthesized compound for one of the predicted structures matched the purified compound in both chemical structure and AHR pharmacology. Our study provides evidence that kynurenine acts as an AHR pro-ligand, which requires novel chemical conversions to act as a receptor agonist. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors

NASA Astrophysics Data System (ADS)

Andersson, Patrik; McGuire, Jacqueline; Rubio, Carlos; Gradin, Katarina; Whitelaw, Murray L.; Pettersson, Sven; Hanberg, Annika; Poellinger, Lorenz

2002-07-01

The dioxin/aryl hydrocarbon receptor (AhR) functions as a ligand-activated transcription factor regulating transcription of a battery of genes encoding xenobiotic metabolizing enzymes. Known receptor ligands are environmental pollutants including polycyclic aromatic hydrocarbons and polychlorinated dioxins. Loss-of-function (gene-disruption) studies in mice have demonstrated that the AhR is involved in toxic effects of dioxins but have not yielded unequivocal results concerning the physiological function of the receptor. Gain-of-function studies therefore were performed to unravel the biological functions of the AhR. A constitutively active AhR expressed in transgenic mice reduced the life span of the mice and induced tumors in the glandular part of the stomach, demonstrating the oncogenic potential of the AhR and implicating the receptor in regulation of cell proliferation.

Novel cellular targets of AhR underlie alterations in neutrophilic inflammation and iNOS expression during influenza virus infection

PubMed Central

Head Wheeler, Jennifer L.; Martin, Kyle C.; Lawrence, B. Paige

2012-01-01

The underlying reasons for variable clinical outcomes from respiratory viral infections remain uncertain. Several studies suggest that environmental factors contribute to this variation, but limited knowledge of cellular and molecular targets of these agents hampers our ability to quantify or modify their contribution to disease and improve public health. The aryl hydrocarbon receptor (AhR) is an environment sensing transcription factor that binds many anthropogenic and natural chemicals. The immunomodulatory properties of AhR ligands are best characterized with extensive studies of changes in CD4+ T cell responses. Yet, AhR modulates other aspects of immune function. We previously showed that during influenza virus infection, AhR activation modulates neutrophil accumulation in the lung, and this contributes to increased mortality in mice. Enhanced levels of inducible nitric oxide synthase (iNOS) in infected lungs are observed during the same timeframe as AhR-mediated increased pulmonary neutrophilia. In this study, we evaluated whether these two consequences of AhR activation are causally linked. Reciprocal inhibition of AhR-mediated elevations in iNOS and pulmonary neutrophilia reveal that, although they are contemporaneous, they are not causally related. We show using Cre/loxP technology that elevated iNOS levels and neutrophil number in the infected lung result from separate, AhR-dependent signaling in endothelial and respiratory epithelial cells, respectively. Studies using mutant mice further reveal that AhR-mediated alterations in these innate responses to infection require a functional nuclear localization signal and DNA binding domain. Thus, gene targets of AhR in non-hematopoietic cells are important new considerations for understanding AhR-mediated changes in innate anti-viral immunity. PMID:23233726

Dynamic gene expression changes precede dioxin-induced liver pathogenesis in medaka fish.

PubMed

Volz, David C; Hinton, David E; Law, J McHugh; Kullman, Seth W

2006-02-01

A major challenge for environmental genomics is linking gene expression to cellular toxicity and morphological alteration. Herein, we address complexities related to hepatic gene expression responses after a single injection of the aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and illustrate an initial stress response followed by cytologic and adaptive changes in the teleost fish medaka. Using a custom 175-gene array, we find that overall hepatic gene expression and histological changes are strongly dependent on dose and time. The most pronounced dioxin-induced gene expression changes occurred early and preceded morphologic alteration in the liver. Following a systematic search for putative Ah response elements (AHREs) (5'-CACGCA-3') within 2000 bp upstream of the predicted transcriptional start site, the majority (87%) of genes screened in this study did not contain an AHRE, suggesting that gene expression was not solely dependent on AHRE-mediated transcription. Moreover, in the highest dosage, we observed gene expression changes associated with adaptation that persisted for almost two weeks, including induction of a gene putatively identified as ependymin that may function in hepatic injury repair. These data suggest that the cellular response to dioxin involves both AHRE- and non-AHRE-mediated transcription, and that coupling gene expression profiling with analysis of morphologic pathogenesis is essential for establishing temporal relationships between transcriptional changes, toxicity, and adaptation to hepatic injury.

Cytochrome P4501A induction in avian hepatocyte cultures exposed to polychlorinated biphenyls: Comparisons with AHR1-mediated reporter gene activity and in ovo toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Manning, Gillian E., E-mail: gmann017@uottawa.ca; Environment Canada, National Wildlife Research Centre, Ottawa, ON, Canada K1A 0H3; Mundy, Lukas J., E-mail: lukas.mundy@ec.gc.ca

2013-01-01

Avian-specific toxic equivalency factors (TEFs) were developed by the World Health Organization to simplify environmental risk assessments of dioxin-like compounds (DLCs), but TEFs do not account for differences in the toxic and biochemical potencies of DLCs among species of birds. Such variability may be due to differences in species sensitivity to individual DLCs. The sensitivity of avian species to DLCs was recently associated with the identity of amino acids 324 and 380 in the aryl hydrocarbon receptor 1 (AHR1) ligand binding domain. A luciferase reporter gene (LRG) assay, measuring AHR1-mediated induction of a cytochrome P450 1A5 (CYP1A5) reporter gene, inmore » combination with a species' AHR1 ligand binding domain sequence, were also shown to predict avian species sensitivity to polychlorinated biphenyls (PCBs) and PCB relative potency in a given species. The goals of the present study were to (1) characterize the concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and PCBs 126, 77, 105 and 118 on induction of ethoxyresorufin O-deethylase (EROD) activity and CYP1A4/5 mRNA in chicken, ring-necked pheasant and Japanese quail embryo hepatocytes and (2) compare these in vitro results to those previously generated by the LRG assay and in ovo toxicity studies. EROD activity and CYP1A4/5 mRNA expression data support and complement the findings of the LRG assay. CYP1A enzyme activity and mRNA expression were significantly correlated both with luciferase activity and in ovo toxicity induced by PCBs. Relative potency values were generally similar between the LRG and EROD assays and indicate that the relative potency of some PCBs may differ among species. -- Highlights: ► The chicken isn't the most sensitive species to CYP1A induction by PCB 105 and 118. ► The relative potency of PCBs differs between avian species. ► EROD activity was correlated with luciferase activity from the LRG assay. ► EROD activity was a better predictor of toxicity

Genome-Wide Meta-Analysis Identifies Regions on 7p21 (AHR) and 15q24 (CYP1A2) As Determinants of Habitual Caffeine Consumption

PubMed Central

Azzato, Elizabeth M.; Bennett, Siiri N.; Berndt, Sonja I.; Boerwinkle, Eric; Chanock, Stephen; Chatterjee, Nilanjan; Couper, David; Curhan, Gary; Heiss, Gerardo; Hu, Frank B.; Hunter, David J.; Jacobs, Kevin; Jensen, Majken K.; Kraft, Peter; Landi, Maria Teresa; Nettleton, Jennifer A.; Purdue, Mark P.; Rajaraman, Preetha; Rimm, Eric B.; Rose, Lynda M.; Rothman, Nathaniel; Silverman, Debra; Stolzenberg-Solomon, Rachael; Subar, Amy; Yeager, Meredith; Chasman, Daniel I.; van Dam, Rob M.; Caporaso, Neil E.

2011-01-01

We report the first genome-wide association study of habitual caffeine intake. We included 47,341 individuals of European descent based on five population-based studies within the United States. In a meta-analysis adjusted for age, sex, smoking, and eigenvectors of population variation, two loci achieved genome-wide significance: 7p21 (P = 2.4×10−19), near AHR, and 15q24 (P = 5.2×10−14), between CYP1A1 and CYP1A2. Both the AHR and CYP1A2 genes are biologically plausible candidates as CYP1A2 metabolizes caffeine and AHR regulates CYP1A2. PMID:21490707

Simulator for SUPO, a Benchmark Aqueous Homogeneous Reactor (AHR)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Klein, Steven Karl; Determan, John C.

2015-10-14

A simulator has been developed for SUPO (Super Power) an aqueous homogeneous reactor (AHR) that operated at Los Alamos National Laboratory (LANL) from 1951 to 1974. During that period SUPO accumulated approximately 600,000 kWh of operation. It is considered the benchmark for steady-state operation of an AHR. The SUPO simulator was developed using the process that resulted in a simulator for an accelerator-driven subcritical system, which has been previously reported.

Estimation of weekly 99Mo production by AHR 200 kW

NASA Astrophysics Data System (ADS)

Siregar, I. H.; Suharyana; Khakim, A.; Siregar, D.; Frida, A. R.

2016-11-01

The estimation of weekly 99Mo production by AHR 200 kW fueled with Low Enriched Uranium Uranyl Nitrate solution has been simulated by using MCNPX computer code. We have employed the AHR design of Babcock & Wilcox Medical Isotope Production System with 9Be Reflector and Stainless steel vessel. We found that when the concentration of uranium in the fresh fuel was 108 gr U/L of UO2(NO3)2 fuel solution, the multiplication factor was 1.0517. The 99Mo concentration reached saturated at tenth day operation. The AHR can produce approximately 1.96×103 6-day-Ci weekly.

Intersection of AHR and Wnt Signaling in Development, Health, and Disease

PubMed Central

Schneider, Andrew J.; Branam, Amanda M.; Peterson, Richard E.

2014-01-01

The AHR (aryl hydrocarbon receptor) and Wnt (wingless-related MMTV integration site) signaling pathways have been conserved throughout evolution. Appropriately regulated signaling through each pathway is necessary for normal development and health, while dysregulation can lead to developmental defects and disease. Though both pathways have been vigorously studied, there is relatively little research exploring the possibility of crosstalk between these pathways. In this review, we provide a brief background on (1) the roles of both AHR and Wnt signaling in development and disease, and (2) the molecular mechanisms that characterize activation of each pathway. We also discuss the need for careful and complete experimental evaluation of each pathway and describe existing research that explores the intersection of AHR and Wnt signaling. Lastly, to illustrate in detail the intersection of AHR and Wnt signaling, we summarize our recent findings which show that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced disruption of Wnt signaling impairs fetal prostate development. PMID:25286307

Transcriptomic assessment of resistance to effects of an aryl hydrocarbon receptor (AHR) agonist in embryos of Atlantic killifish (Fundulus heteroclitus) from a marine Superfund site.

PubMed

Oleksiak, Marjorie F; Karchner, Sibel I; Jenny, Matthew J; Franks, Diana G; Welch, David B Mark; Hahn, Mark E

2011-05-24

Populations of Atlantic killifish (Fundulus heteroclitus) have evolved resistance to the embryotoxic effects of polychlorinated biphenyls (PCBs) and other halogenated and nonhalogenated aromatic hydrocarbons that act through an aryl hydrocarbon receptor (AHR)-dependent signaling pathway. The resistance is accompanied by reduced sensitivity to induction of cytochrome P450 1A (CYP1A), a widely used biomarker of aromatic hydrocarbon exposure and effect, but whether the reduced sensitivity is specific to CYP1A or reflects a genome-wide reduction in responsiveness to all AHR-mediated changes in gene expression is unknown. We compared gene expression profiles and the response to 3,3',4,4',5-pentachlorobiphenyl (PCB-126) exposure in embryos (5 and 10 dpf) and larvae (15 dpf) from F. heteroclitus populations inhabiting the New Bedford Harbor, Massachusetts (NBH) Superfund site (PCB-resistant) and a reference site, Scorton Creek, Massachusetts (SC; PCB-sensitive). Analysis using a 7,000-gene cDNA array revealed striking differences in responsiveness to PCB-126 between the populations; the differences occur at all three stages examined. There was a sizeable set of PCB-responsive genes in the sensitive SC population, a much smaller set of PCB-responsive genes in NBH fish, and few similarities in PCB-responsive genes between the two populations. Most of the array results were confirmed, and additional PCB-regulated genes identified, by RNA-Seq (deep pyrosequencing). The results suggest that NBH fish possess a gene regulatory defect that is not specific to one target gene such as CYP1A but rather lies in a regulatory pathway that controls the transcriptional response of multiple genes to PCB exposure. The results are consistent with genome-wide disruption of AHR-dependent signaling in NBH fish.

Transcriptomic assessment of resistance to effects of an aryl hydrocarbon receptor (AHR) agonist in embryos of Atlantic killifish (Fundulus heteroclitus) from a marine Superfund site

PubMed Central

2011-01-01

Background Populations of Atlantic killifish (Fundulus heteroclitus) have evolved resistance to the embryotoxic effects of polychlorinated biphenyls (PCBs) and other halogenated and nonhalogenated aromatic hydrocarbons that act through an aryl hydrocarbon receptor (AHR)-dependent signaling pathway. The resistance is accompanied by reduced sensitivity to induction of cytochrome P450 1A (CYP1A), a widely used biomarker of aromatic hydrocarbon exposure and effect, but whether the reduced sensitivity is specific to CYP1A or reflects a genome-wide reduction in responsiveness to all AHR-mediated changes in gene expression is unknown. We compared gene expression profiles and the response to 3,3',4,4',5-pentachlorobiphenyl (PCB-126) exposure in embryos (5 and 10 dpf) and larvae (15 dpf) from F. heteroclitus populations inhabiting the New Bedford Harbor, Massachusetts (NBH) Superfund site (PCB-resistant) and a reference site, Scorton Creek, Massachusetts (SC; PCB-sensitive). Results Analysis using a 7,000-gene cDNA array revealed striking differences in responsiveness to PCB-126 between the populations; the differences occur at all three stages examined. There was a sizeable set of PCB-responsive genes in the sensitive SC population, a much smaller set of PCB-responsive genes in NBH fish, and few similarities in PCB-responsive genes between the two populations. Most of the array results were confirmed, and additional PCB-regulated genes identified, by RNA-Seq (deep pyrosequencing). Conclusions The results suggest that NBH fish possess a gene regulatory defect that is not specific to one target gene such as CYP1A but rather lies in a regulatory pathway that controls the transcriptional response of multiple genes to PCB exposure. The results are consistent with genome-wide disruption of AHR-dependent signaling in NBH fish. PMID:21609454

Targeted mutagenesis of aryl hydrocarbon receptor 2a and 2b genes in Atlantic killifish (Fundulus heteroclitus)

PubMed Central

Aluru, Neelakanteswar; Karchner, Sibel I.; Franks, Diana G.; Nacci, Diane; Champlin, Denise; Hahn, Mark E.

2014-01-01

Understanding molecular mechanisms of toxicity is facilitated by experimental manipulations, such as disruption of function by gene targeting, that are especially challenging in non-standard model species with limited genomic resources. While loss-of-function approaches have included gene knock-down using morpholino-modified oligonucleotides and random mutagenesis using mutagens or retroviruses, more recent approaches include targeted mutagenesis using zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technology. These latter methods provide more accessible opportunities to explore gene function in non-traditional model species. To facilitate evaluations of toxic mechanisms for important categories of aryl hydrocarbon pollutants, whose actions are known to be receptor mediated, we used ZFN and CRISPR-Cas9 approaches to generate aryl hydrocarbon receptor 2a (AHR2a) and AHR2b gene mutations in Atlantic killifish (Fundulus heteroclitus) embryos. This killifish is a particularly valuble non-traditional model for this study, with multiple paralogs of AHR whose functions are not well characterized. In addition, some populations of this species have evolved resistance to toxicants such as halogenated aromatic hydrocarbons. AHR-null killifish will be valuable for characterizing the role of the individual AHR paralogs in evolved resistance, as well as in normal development. We first used five-finger ZFNs targeting exons 1 and 3 of AHR2a. Subsequently, CRISPR-Cas9 guide RNAs were designed to target regions in exon 2 and 3 of AHR2a and AHR2b. We successfully induced frameshift mutations in AHR2a exon 3 with ZFN and CRISPR-Cas9 guide RNAs, with mutation frequencies of 10% and 16%, respectively. In AHR2b, mutations were induced using CRISPR-Cas9 guide RNAs targeting sites in both exon 2 (17%) and exon 3 (63%). We screened AHR2b exon 2 CRISPR-Cas9-injected embryos for

Macrophages from Behcet's Disease Patients Express Decreased Level of Aryl Hydrocarbon Receptor (AHR) mRNA.

PubMed

Palizgir, Mohammad Taghi; Akhtari, Maryam; Mahmoudi, Mahdi; Mostafaei, Shayan; Rezaeimanesh, Alireza; Akhlaghi, Massoomeh; Shahram, Farhad

2017-10-01

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, connecting environmental stimulators with the immune system. M1 macrophages are a part of immune system that contribute to the inflammatory events in the pathogenesis of Behcet's disease (BD). The effect of AHR on the macrophages in BD patients is still unclear. In this study, we investigated the mRNA expression of AHR in the monocyte-derived and M1 macrophages in active BD patients in comparison to healthy controls. Isolated monocytes from 10 healthy controls and 10 active BD patients were differentiated to macrophages by macrophage-colony stimulating factor (M-CSF) for 7 days. Cells were then polarized to M1 macrophages by lipopolysaccharide (LPS) and interferon-γ (IFNγ) for 24h. Monocyte purity and macrophage markers expression were analyzed by flow cytometry. Analysis of AHR mRNA expression was performed by SYBR Green real-time PCR. Our results showed that AHR expression is significantly down-regulated in M1 macrophages compare to monocyte-derived macrophages. It was shown that both monocyte-derived macrophages and M1 macrophages from BD patients significantly express lower level of AHR mRNA compared to healthy individuals. Our results demonstrate an anti-inflammatory role for AHR in macrophages, which suggest that decreased AHR expression is associated with pro-inflammatory M1 macrophage and BD susceptibility.

Ahr2-dependance of PCB126 effects on the swimbladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish

PubMed Central

Jönsson, Maria E.; Kubota, Akira; Timme-Laragy, Alicia; Woodin, Bruce; Stegeman, John J.

2012-01-01

The teleost swimbladder is assumed a homolog of the tetrapod lung. Both swimbladder and lung are developmental targets of persistent aryl hydrocarbon receptor (AHR1) agonists; in zebrafish (Danio rerio) the swimbladder fails to inflate with exposure to 3,3’,4,4’,5-pentachlorobiphenyl (PCB126). The mechanism for this effect is unknown, but studies have suggested roles of cytochrome P4501 (CYP1) and cyclooxygenase 2 (Cox-2) in some Ahr-mediated developmental effects in zebrafish. We determined relationships between swimbladder inflation and CYP1 and Cox-2 mRNA expression in PCB126-exposed zebrafish embryos. We also examined effects on β-catenin dependent transcription, histological effects, and Ahr2 dependance of the effect of PCB126 on swimbladder using morpholinos targeting ahr2. One-day-old embryos were exposed to waterborne PCB126 or carrier (DMSO) for 24 h and then held in clean water until day 4, a normal time for swimbladder inflation. The effects of PCB126 were concentration-dependent with EC50 values of 1.4 to 2.0 nM for induction of the CYP1s, 3.7 and 5.1 nM (or higher) for cox-2a and cox-2b induction, and 2.5 nM for inhibition of swimbladder inflation. Histological defects included a compaction of the developing bladder. Ahr2-morpholino treatment rescued the effect of PCB126 (5 nM) on swimbladder inflation and blocked induction of CYP1A, cox-2a, and cox-2b. With 2 nM PCB126 approximately 30% of eleutheroembryos2 failed to inflate the swimbladder, but there was no difference in CYP1 or cox-2 mRNA expression between those embryos and embryos showing inflated swimbladder. Our results indicate that PCB126 blocks swimbladder inflation via an Ahr2-mediated mechanism. This mechanism seems independent of CYP1 or cox-2 mRNA induction but may involve abnormal development of swimbladder cells. PMID:23036320

Advanced lead acid battery development project. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1997-02-01

This project involved laboratory and road testing of the Horizon (registered) advanced lead acid batteries produced by Electrosource, Inc. A variety of electric vehicles in the fleet operated by the Sacramento Municipal Utility District and McClellan Air Force Base were used for road tests. The project was sponsored by the Defense Advanced Research Projects Agency under RA 93-23 entitled Electric Vehicle Technology and Infrastructure. The Horizon battery is a valve regulated, or sealed, lead acid battery produced in a variety of sizes and performance levels. During the project, several design and process improvements on the Horizon battery resulted in amore » production battery with a specific energy approaching 45 watt-hours per kilogram (Whr/kg) capable of delivering a peak current of 450 amps. The 12 volt, 95 amp-hour (Ahr) Horizon battery, model number 12N95, was placed into service in seven (7) test vehicles, including sedans, prototype lightweight electric vehicles, and passenger vans. Over 20,000 miles have been driven to date on vehicles powered by the Horizon battery. Road test results indicate that when the battery pack is used with a compatible charger and charge management system, noticeably improved acceleration characteristics are evident, and the vehicles provide a useful range almost 20% greater than with conventional lead-acid batteries.« less

The aryl hydrocarbon receptor repressor - More than a simple feedback inhibitor of AhR signaling: Clues for its role in inflammation and cancer.

PubMed

Vogel, Christoph F A; Haarmann-Stemmann, Thomas

2017-02-01

The aryl hydrocarbon receptor repressor (AhRR) was first described as a specific competitive repressor of aryl hydrocarbon receptor (AhR) activity based on its ability to dimerize with the AhR nuclear translocator (ARNT) and through direct competition of AhR/ARNT and AhRR/ARNT complexes for binding to dioxin-responsive elements (DREs). Like AhR, AhRR belongs to the basic Helix-Loop-Helix/Per-ARNT-Sim (bHLH/PAS) protein family but lacks functional ligand-binding and transactivation domains. Transient transfection experiments with ARNT and AhRR mutants examining the inhibitory mechanism of AhRR suggested a more complex mechanism than the simple mechanism of negative feedback through sequestration of ARNT to regulate AhR signaling. Recently, AhRR has been shown to act as a tumor suppressor gene in several types of cancer cells. Furthermore, epidemiological studies have found epigenetic changes and silencing of AhRR associated with exposure to cigarette smoke and cancer development. Additional studies from our laboratories have demonstrated that AhRR represses other signaling pathways including NF-κB and is capable of regulating inflammatory responses. A better understanding of the regulatory mechanisms of AhRR in AhR signaling and adverse outcome pathways leading to deregulated inflammatory responses contributing to tumor promotion and other adverse health effects is expected from future studies. This review article summarizes the characteristics of AhRR as an inhibitor of AhR activity and highlights more recent findings pointing out the role of AhRR in inflammation and tumorigenesis.

Mars Mission Surface Operation Simulation Testing of Lithium-Ion Batteries

NASA Technical Reports Server (NTRS)

Smart, M. C.; Bugga, R.; Whitcanack, L. D.; Chin, K. B.; Davies, E. D.; Surampudi, S.

2003-01-01

The objectives of this program are to 1) Assess viability of using lithium-ion technology for future NASA applications, with emphasis upon Mars landers and rovers which will operate on the planetary surface; 2) Support the JPL 2003 Mars Exploration Rover program to assist in the delivery and testing of a 8 AHr Lithium-Ion battery (Lithion/Yardney) which will power the rover; 3) Demonstrate applicability of using lithium-ion technologyfor future Mars applications: Mars 09 Science Laboratory (Smart Lander) and Future Mars Surface Operations (General). Mission simulation testing was carried out for cells and batteries on the Mars Surveyor 2001 Lander and the 2003 Mars Exploration Rover.

Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moyer, Benjamin J.

Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHRmore » antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor β1 (TGFβ1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFβ1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR with its broad ligand binding

Functional and phenotypic effects of AhR activation in inflammatory dendritic cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bankoti, Jaishree; Center for Environmental Health Sciences, University of Montana, Missoula, MT; Rase, Ben

2010-07-15

Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces immune suppression. Dendritic cells (DCs) are key antigen presenting cells governing T cell activation and differentiation. However, the consequences of AhR activation in DCs are not fully defined. We hypothesized that AhR activation alters DC differentiation and generates dysfunctional DCs. To test this hypothesis, inflammatory bone marrow-derived DCs (BMDCs) from C57Bl/6 mice were generated in the presence of vehicle or TCDD. TCDD decreased CD11c expression but increased MHC class II, CD86 and CD25 expression on the BMDCs. The effects of TCDD were strictly AhR-dependent but not exclusively DRE-mediated. Similar effects weremore » observed with two natural AhR ligands, 6-formylindolo[3,2-b]carbazole (FICZ) and 2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid (ITE). TCDD increased LPS- and CpG-induced IL-6 and TNF-{alpha} production by BMDCs but decreased their NO production. TCDD decreased CpG-induced IL-12p70 production by BMDCs but did not affect their secretion of IL-10. TCDD downregulated LPS- and CpG-induced NF-kB p65 levels and induced a trend towards upregulation of RelB levels in the BMDCs. AhR activation by TCDD modulated BMDC uptake of both soluble and particulate antigens. Induction of indoleamine-2,3-dioxygenase (IDO) and TGF-{beta}3 has been implicated in the generation of regulatory T cells following AhR activation. TCDD increased IDO1, IDO2 and TGF-{beta}3 mRNA levels in BMDCs as compared to vehicle. Despite the induction of regulatory mediators, TCDD-treated BMDCs failed to suppress antigen-specific T cell activation. Thus, AhR activation can directly alter the differentiation and innate functions of inflammatory DCs without affecting their ability to successfully interact with T cells.« less

Crucial Role of the Aryl Hydrocarbon Receptor (AhR) in Indoxyl Sulfate-Induced Vascular Inflammation.

PubMed

Ito, Shunsuke; Osaka, Mizuko; Edamatsu, Takeo; Itoh, Yoshiharu; Yoshida, Masayuki

2016-08-01

The aryl hydrocarbon receptor (AhR), a ligand-inducible transcription factor mediating toxic effects of dioxins and uremic toxins, has recently emerged as a pathophysiological regulator of immune-inflammatory conditions. Indoxyl sulfate, a uremic toxin, is associated with cardiovascular disease in patients with chronic kidney disease and has been shown to be a ligand for AhR. The aim of this study was to investigate the potential role of AhR in indoxyl sulfate-induced leukocyte-endothelial interactions. Endothelial cell-specific AhR knockout (eAhR KO) mice were produced by crossing AhR floxed mice with Tie2 Cre mice. Indoxyl sulfate was administered for 2 weeks, followed by injection of TNF-α. Leukocyte recruitment to the femoral artery was assessed by intravital microscopy. Vascular endothelial cells were transfected with siRNA specific to AhR (siAhR) and treated with indoxyl sulfate, followed by stimulation with TNF-α. Indoxyl sulfate dramatically enhanced TNF-α-induced leukocyte recruitment to the vascular wall in control animals but not in eAhR KO mice. In endothelial cells, siAhR significantly reduced indoxyl sulfate-enhanced leukocyte adhesion as well as E-selectin expression, whereas the activation of JNK and nuclear factor-κB was not affected. A luciferase assay revealed that the region between －153 and －146 bps in the E-selectin promoter was responsible for indoxyl sulfate activity via AhR. Mutational analysis of this region revealed that activator protein-1 (AP-1) is responsible for indoxyl sulfate-triggered E-selectin expression via AhR. AhR mediates indoxyl sulfate-enhanced leukocyte-endothelial interactions through AP-1 transcriptional activity, which may constitute a new mechanism of vascular inflammation in patients with renal disease.

Cell and region specificity of Aryl hydrocarbon Receptor (AhR) system in the testis and the epididymis.

PubMed

Wajda, A; Łapczuk, J; Grabowska, M; Pius-Sadowska, E; Słojewski, M; Laszczynska, M; Urasinska, E; Machalinski, B; Drozdzik, M

2017-04-01

Aryl hydrocarbon receptor (AhR) plays multiple important functions in adaptive responses. Exposure to AhR ligands may produce an altered metabolic activity controlled by the AhR pathways, and consequently affect drug/toxin responses, hormonal status and cellular homeostasis. This research revealed species-, cell- and region-specific pattern of the AhR system expression in the rat and human testis and epididymis, complementing the existing knowledge, especially within the epididymal segments. The study showed that AhR level in the rat and human epididymis is higher than in the testis. The downregulation of AhR expression after TCDD treatment was revealed in the spermatogenic cells at different stages and the epididymal epithelial cells, but not in the Sertoli and Leydig cells. Hence, this basic research provides information about the AhR function in the testis and epididymis, which may provide an insight into deleterious effects of drugs, hormones and environmental pollutants on male fertility. Copyright © 2017 Elsevier Inc. All rights reserved.

New CYP1 genes in the frog Xenopus (Silurana) tropicalis: Induction patterns and effects of AHR agonists during development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Joensson, Maria E., E-mail: maria.jonsson@ebc.uu.se; Biology Department, Redfield 3-42 MS 32, Woods Hole Oceanographic Institution, Woods Hole, MA, 02543; Berg, Cecilia

2011-01-15

The Xenopus tropicalis genome shows a single gene in each of the four cytochrome P450 1 (CYP1) subfamilies that occur in vertebrates, designated as CYP1A, CYP1B1, CYP1C1, and CYP1D1. We cloned the cDNAs of these genes and examined their expression in untreated tadpoles and in tadpoles exposed to waterborne aryl hydrocarbon receptor agonists, 3,3',4,4',5-pentachlorobiphenyl (PCB126), {beta}-naphthoflavone ({beta}NF), or indigo. We also examined the effects of PCB126 on expression of genes involved in stress response, cell proliferation, thyroid homeostasis, and prostaglandin synthesis. PCB126 induced CYP1A, CYP1B1, and CYP1C1 but had little effect on CYP1D1 (77-, 1.7-, 4.6- and 1.4-fold induction versusmore » the control, respectively). {beta}NF induced CYP1A and CYP1C1 (26- and 2.5-fold), while, under conditions used, indigo tended to induce only CYP1A (1.9-fold). The extent of CYP1 induction by PCB126 and {beta}NF was positively correlated to the number of putative dioxin response elements 0-20 kb upstream of the start codons. No morphological effect was observed in tadpoles exposed to 1 nM-10 {mu}M PCB126 at two days post-fertilization (dpf) and screened 20 days later. However, in 14-dpf tadpoles a slight up-regulation of the genes for PCNA, transthyretin, HSC70, Cu-Zn SOD, and Cox-2 was observed two days after exposure to 1 {mu}M PCB126. This study of the full suite of CYP1 genes in an amphibian species reveals gene- and AHR agonist-specific differences in response, as well as a much lower sensitivity to CYP1 induction and short-term toxicity by PCB126 compared with in fish larvae. The single genes in each CYP1 subfamily may make X. tropicalis a useful model for mechanistic studies of CYP1 functions.« less

Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jönsson, Maria E., E-mail: maria.jonsson@ebc.uu.se; Biology Department, Redfield 3-42 MS 32, Woods Hole Oceanographic Institution, Woods Hole, MA, 02543; Kubota, Akira, E-mail: akubota@whoi.edu

2012-12-01

The teleost swim bladder is assumed a homolog of the tetrapod lung. Both swim bladder and lung are developmental targets of persistent aryl hydrocarbon receptor (AHR) agonists; in zebrafish (Danio rerio) the swim bladder fails to inflate with exposure to 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). The mechanism for this effect is unknown, but studies have suggested roles of cytochrome P450 1 (CYP1) and cyclooxygenase 2 (Cox-2) in some Ahr-mediated developmental effects in zebrafish. We determined relationships between swim bladder inflation and CYP1 and Cox-2 mRNA expression in PCB126-exposed zebrafish embryos. We also examined effects on β-catenin dependent transcription, histological effects, and Ahr2 dependencemore » of the effect of PCB126 on swim bladder using morpholinos targeting ahr2. One-day-old embryos were exposed to waterborne PCB126 or carrier (DMSO) for 24 h and then held in clean water until day 4, a normal time for swim bladder inflation. The effects of PCB126 were concentration-dependent with EC{sub 50} values of 1.4 to 2.0 nM for induction of the CYP1s, 3.7 and 5.1 nM (or higher) for cox-2a and cox-2b induction, and 2.5 nM for inhibition of swim bladder inflation. Histological defects included a compaction of the developing bladder. Ahr2-morpholino treatment rescued the effect of PCB126 (5 nM) on swim bladder inflation and blocked induction of CYP1A, cox-2a, and cox-2b. With 2 nM PCB126 approximately 30% of eleutheroembryos failed to inflate the swim bladder, but there was no difference in CYP1 or cox-2 mRNA expression between those embryos and embryos showing inflated swim bladder. Our results indicate that PCB126 blocks swim bladder inflation via an Ahr2-mediated mechanism. This mechanism seems independent of CYP1 or cox-2 mRNA induction but may involve abnormal development of swim bladder cells. -- Highlights: ► PCB126 caused cellular changes in the developing swim bladder. ► Swim bladder inflation was not related to expression of CYP1

The AhR agonist VAF347 augments retinoic acid-induced differentiation in leukemia cells

PubMed Central

Ibabao, Christopher N.; Bunaciu, Rodica P.; Schaefer, Deanna M.W.; Yen, Andrew

2015-01-01

In binary cell-fate decisions, driving one lineage and suppressing the other are conjoined. We have previously reported that aryl hydrocarbon receptor (AhR) promotes retinoic acid (RA)-induced granulocytic differentiation of lineage bipotent HL-60 myeloblastic leukemia cells. VAF347, an AhR agonist, impairs the development of CD14+CD11b+ monocytes from granulo-monocytic (GM) stage precursors. We thus hypothesized that VAF347 propels RA-induced granulocytic differentiation and impairs D3-induced monocytic differentiation of HL-60 cells. Our results show that VAF347 enhanced RA-induced cell cycle arrest, CD11b integrin expression and neutrophil respiratory burst. Granulocytic differentiation is known to be driven by MAPK signaling events regulated by Fgr and Lyn Src-family kinases, the CD38 cell membrane receptor, the Vav1 GEF, the c-Cbl adaptor, as well as AhR, all of which are embodied in a putative signalsome. We found that the VAF347 AhR ligand regulates the signalsome. VAF347 augments RA-induced expression of AhR, Lyn, Vav1, and c-Cbl as well as p47phox. Several interactions of partners in the signalsome appear to be enhanced: Fgr interaction with c-Cbl, CD38, and with pS259c-Raf and AhR interaction with c-Cbl and Lyn. Thus, we report that, while VAF347 impedes monocytic differentiation induced by 1,25-dihydroxyvitamin D3, VAF347 promotes RA-induced differentiation. This effect seems to involve but not to be limited to Lyn, Vav1, c-Cbl, AhR, and Fgr. PMID:25941627

The AhR agonist VAF347 augments retinoic acid-induced differentiation in leukemia cells.

PubMed

Ibabao, Christopher N; Bunaciu, Rodica P; Schaefer, Deanna M W; Yen, Andrew

2015-01-01

In binary cell-fate decisions, driving one lineage and suppressing the other are conjoined. We have previously reported that aryl hydrocarbon receptor (AhR) promotes retinoic acid (RA)-induced granulocytic differentiation of lineage bipotent HL-60 myeloblastic leukemia cells. VAF347, an AhR agonist, impairs the development of CD14(+)CD11b(+) monocytes from granulo-monocytic (GM) stage precursors. We thus hypothesized that VAF347 propels RA-induced granulocytic differentiation and impairs D3-induced monocytic differentiation of HL-60 cells. Our results show that VAF347 enhanced RA-induced cell cycle arrest, CD11b integrin expression and neutrophil respiratory burst. Granulocytic differentiation is known to be driven by MAPK signaling events regulated by Fgr and Lyn Src-family kinases, the CD38 cell membrane receptor, the Vav1 GEF, the c-Cbl adaptor, as well as AhR, all of which are embodied in a putative signalsome. We found that the VAF347 AhR ligand regulates the signalsome. VAF347 augments RA-induced expression of AhR, Lyn, Vav1, and c-Cbl as well as p47(phox). Several interactions of partners in the signalsome appear to be enhanced: Fgr interaction with c-Cbl, CD38, and with pS259c-Raf and AhR interaction with c-Cbl and Lyn. Thus, we report that, while VAF347 impedes monocytic differentiation induced by 1,25-dihydroxyvitamin D3, VAF347 promotes RA-induced differentiation. This effect seems to involve but not to be limited to Lyn, Vav1, c-Cbl, AhR, and Fgr.

Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1.

PubMed

Moyer, Benjamin J; Rojas, Itzel Y; Kerley-Hamilton, Joanna S; Hazlett, Haley F; Nemani, Krishnamurthy V; Trask, Heidi W; West, Rachel J; Lupien, Leslie E; Collins, Alan J; Ringelberg, Carol S; Gimi, Barjor; Kinlaw, William B; Tomlinson, Craig R

2016-06-01

Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor β1 (TGFβ1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFβ1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR with its broad ligand binding specificity

Effects of artificial sweeteners on the AhR- and GR-dependent CYP1A1 expression in primary human hepatocytes and human cancer cells.

PubMed

Kamenickova, Alzbeta; Pecova, Michaela; Bachleda, Petr; Dvorak, Zdenek

2013-12-01

Food constituents may cause a phenomenon of food-drug interactions. In the current study, we examined the effects of artificial sweeteners (aspartame, acesulfame, cyclamate, saccharin) on the aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR)-dependent expression of CYP1A1 in human hepatocytes, hepatic HepG2 and intestinal LS174T cancer cell lines. Sweeteners were tested in concentrations up to those occurring in non-alcoholic beverages. Basal and ligand-inducible AhR- and GR-dependent reporter gene activation in stably transfected HepG2 and HeLa cells, respectively, were not affected by either of the sweeteners tested after 24h of incubation. The expression of CYP1A1 mRNA and protein in primary cultures of human hepatocytes and in LS174T and HepG2 cells was not induced by any of the tested sweeteners. Overall, aspartame, acesulfame, saccharin and cyclamate had no effects on CYP1A1 expression and transcriptional activities of AhR and GR. These data imply the safety of artificial sweeteners in terms of interference with AhR, GR and CYP1A1. Copyright © 2013 Elsevier Ltd. All rights reserved.

NcoA2-Dependent Inhibition of HIF-1α Activation Is Regulated via AhR.

PubMed

Tsai, Chi-Hao; Li, Ching-Hao; Liao, Po-Lin; Cheng, Yu-Wen; Lin, Cheng-Hui; Huang, Shih-Hsuan; Kang, Jaw-Jou

2015-12-01

High endogenous levels of aryl hydrocarbon receptor (AhR) contribute to hypoxia signaling pathway inhibition following exposure to the potent AhR ligand benzo[a]pyrene (B[a]P) and could alter cellular homeostasis and disease condition. Increasing evidence indicates that AhR might compete with AhR nuclear translocator (ARNT) for complex formation with hypoxia-inducible factor-1α (HIF-1α) for transactivation, which could alter several physiological variables. Nuclear receptor coactivator 2 (NcoA2) is a transcription coactivator that regulates transcription factor activation and inhibition of basic helix-loop-helix Per (Period)-ARNT-SIM (single-minded) (bHLH-PAS) family proteins, such as HIF-1α, ARNT, and AhR, through protein-protein interactions. In this study, we demonstrated that both hypoxia and hypoxia-mimic conditions decreased NcoA2 protein expression in HEK293T cells. Hypoxia response element (HRE) and xenobiotic-responsive element (XRE) transactivation also were downregulated with NcoA2 knockdown under hypoxic conditions. In addition, B[a]P significantly decreased NcoA2 protein expression be accompanied with AhR degradation. We next evaluated whether the absence of AhR could affect NcoA2 protein function under hypoxia-mimetic conditions. NcoA2 and HIF-1α nuclear localization decreased in both B[a]P-pretreated and AhR-knockdown HepG2 cells under hypoxia-mimic conditions. Interestingly, NcoA2 overexpression downregulated HRE transactivation by competing with HIF-1α and AhR to form protein complexes with ARNT. Both NcoA2 knockdown and overexpression inhibited endothelial cell tube formation in vitro. We also demonstrated using the in vivo plug assay that NcoA2-regulated vascularization decreased in mice. Taken together, these results revealed a biphasic role of NcoA2 between AhR and hypoxic conditions, thus providing a novel mechanism underlying the cross talk between AhR and hypoxia that affects disease development and progression. © The Author 2015

Micro124-mediated AHR expression regulates the inflammatory response of chronic rhinosinusitis (CRS) with nasal polyps.

PubMed

Liu, C C; Xia, M; Zhang, Y J; Jin, P; Zhao, L; Zhang, J; Li, T; Zhou, X M; Tu, Y Y; Kong, F; Sun, C; Shi, L; Zhao, M Q

2018-06-02

MicroRNAs represent a component of the innate immune responses that can restrain inflammatory signaling, miR124 is an important member of inflammation-associated miRNAs, and abnormal miR124 expression is observed in many inflammatory diseases and immune disorders. However, the role and signaling pathways of miR124 in chronic rhinosinusitis with nasal polyps (CRSwNPs) have not been studied in detail. The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that is highly conserved in evolution and plays important roles in the inflammatory response process. In our study, we describe the role of miR124 in the inflammatory response of CRS with nasal polyps. We found that the expression of miR124 was decreased in nasal polyps, and negatively correlated with the expression of AHR. MiR124 can inhibit AHR expression by directly target 3' untranslated region (3'-UTR) of AHR. To further investigate the relationship between miR124, AHR and CRS inflammatory response, we transfect HNEpC cells with miR124 mimic, miR124 inhibitors or siRNA of AHR, then all the results showed that miR124 could regulates cellular inflammatory response through negatively regulating AHR expression. This study demonstrated that the regulation of AHR expression by miR124 is critical to the development of inflammatory response in CRSwNPs. Copyright © 2018. Published by Elsevier Inc.

ITE Suppresses Angiogenic Responses in Human Artery and Vein Endothelial Cells: Differential Roles of AhR.

PubMed

Li, Yan; Wang, Kai; Zou, Qing-Yun; Jiang, Yi-Zhou; Zhou, Chi; Zheng, Jing

2017-12-01

Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor is involved in regulation of many essential biological processes including vascular development and angiogenesis. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an AhR ligand, which regulates immune responses and cancer cell growth. However, the roles of the ITE/AhR pathway in mediating placental angiogenesis remains elusive. Here, we determined if ITE affected placental angiogenic responses via AhR in human umbilical vein (HUVECs) and artery endothelial (HUAECs) cells in vitro. We observed that ITE dose- and time-dependently inhibited proliferation and viability of HUAECs and HUVECs, whereas it inhibited migration of HUAECs, but not HUVECs. While AhR siRNA significantly suppressed AhR protein expression in HUVECs and HUAECs, it attenuated the ITE-inhibited angiogenic responses of HUAECs, but not HUVECs. Collectively, ITE suppressed angiogenic responses of HUAECs and HUVECs, dependent and independent of AhR, respectively. These data suggest that ITE may regulate placental angiogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

AhR mediates an anti-inflammatory feedback mechanism in human Langerhans cells involving FcεRI and IDO.

PubMed

Koch, S; Stroisch, T J; Vorac, J; Herrmann, N; Leib, N; Schnautz, S; Kirins, H; Förster, I; Weighardt, H; Bieber, T

2017-11-01

Aryl hydrocarbon receptor (AhR), an important regulator of immune responses, is activated by UVB irradiation in the skin. Langerhans cells (LC) in the epidermis of patients with atopic dermatitis (AD) carry the high-affinity receptor for IgE, FcεRI, and are crucially involved in the pathogenesis of AD by inducing inflammatory responses and regulating tolerogenic processes. We investigated AhR and AhR repressor (AhRR) expression and functional consequences of AhR activation in human ex vivo skin cells and in in vitro-generated LC. Epidermal cells from healthy skin were analyzed for their expression of AhR and AhRR. LC generated from CD34 + hematopoietic stem cells (CD34LC) were treated with the UV photoproduct and AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ). Cell surface receptors, transcription factors, and the tolerogenic tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) were analyzed using flow cytometry and quantitative PCR. Epidermal LC and CD34LC express AhR and AhRR. AhR was also found in keratinocytes, which lack AhRR. AhR activation of LC by FICZ caused downregulation of FcεRI in CD34LC without affecting their maturation. AhR-mediated regulation of FcεRI did not involve any known transcription factors related to this receptor. Furthermore, we could show upregulation of IDO mediated by AhR engagement. Our study shows that AhR activation by FICZ reduces FcεRI and upregulates IDO expression in LC. This AhR-mediated anti-inflammatory feedback mechanism may dampen the allergen-induced inflammation in AD. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Relationships between serum-induced AhR bioactivity or mitochondrial inhibition and circulating polychlorinated biphenyls (PCBs).

PubMed

Park, Wook Ha; Kang, Sora; Lee, Hong Kyu; Salihovic, Samira; Bavel, Bert van; Lind, P Monica; Pak, Youngmi Kim; Lind, Lars

2017-08-24

Metabolic syndrome and mitochondrial dysfunction have been linked to elevated serum levels of persistent organic pollutants (POPs). However, it is not clear which specific POPs contribute to aryl hydrocarbon receptor (AhR)-dependent bioactivity or inhibit mitochondrial function in human subjects. Here, we measured the cumulative bioactivity of AhR ligand mixture (AhR bioactivity) and the effects on mitochondrial function (ATP concentration) in recombinant Hepa1c1c7 cells incubated with raw serum samples obtained from 911 elderly subjects in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Plasma concentrations of 30 POPs and plastic chemicals have previously been determined in the same PIVUS subjects. Linear regression analysis demonstrated that total toxic equivalence (TEQ) values and polychlorinated biphenyls (PCBs) were significantly correlated with AhR bioactivity (positively) and ATP concentration (negatively). Serum AhR bioactivities were positively associated with some PCBs, regardless of their dioxin-like properties, but only dioxin-like PCBs stimulated AhR bioactivity. By contrast, PCBs mediated a reduction in ATP content independently of their dioxin-like properties. This study suggests that AhR bioactivity and ATP concentrations in serum-treated cells may be valuable surrogate biomarkers of POP exposure and could be useful for the estimation of the effects of POPs on human health.

Integration of mouse and human genome-wide association data identifies KCNIP4 as an asthma gene.

PubMed

Himes, Blanca E; Sheppard, Keith; Berndt, Annerose; Leme, Adriana S; Myers, Rachel A; Gignoux, Christopher R; Levin, Albert M; Gauderman, W James; Yang, James J; Mathias, Rasika A; Romieu, Isabelle; Torgerson, Dara G; Roth, Lindsey A; Huntsman, Scott; Eng, Celeste; Klanderman, Barbara; Ziniti, John; Senter-Sylvia, Jody; Szefler, Stanley J; Lemanske, Robert F; Zeiger, Robert S; Strunk, Robert C; Martinez, Fernando D; Boushey, Homer; Chinchilli, Vernon M; Israel, Elliot; Mauger, David; Koppelman, Gerard H; Postma, Dirkje S; Nieuwenhuis, Maartje A E; Vonk, Judith M; Lima, John J; Irvin, Charles G; Peters, Stephen P; Kubo, Michiaki; Tamari, Mayumi; Nakamura, Yusuke; Litonjua, Augusto A; Tantisira, Kelan G; Raby, Benjamin A; Bleecker, Eugene R; Meyers, Deborah A; London, Stephanie J; Barnes, Kathleen C; Gilliland, Frank D; Williams, L Keoki; Burchard, Esteban G; Nicolae, Dan L; Ober, Carole; DeMeo, Dawn L; Silverman, Edwin K; Paigen, Beverly; Churchill, Gary; Shapiro, Steve D; Weiss, Scott T

2013-01-01

Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.

Aryl Hydrocarbon Receptor Plays Protective Roles against High Fat Diet (HFD)-induced Hepatic Steatosis and the Subsequent Lipotoxicity via Direct Transcriptional Regulation of Socs3 Gene Expression*

PubMed Central

Wada, Taira; Sunaga, Hiroshi; Miyata, Kazuki; Shirasaki, Haruno; Uchiyama, Yuki; Shimba, Shigeki

2016-01-01

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor regulating the expression of genes involved in xenobiotic response. Recent studies have suggested that AhR plays essential roles not only in xenobiotic detoxification but also energy metabolism. Thus, in this study, we studied the roles of AhR in lipid metabolism. Under high fat diet (HFD) challenge, liver-specific AhR knock-out (AhR LKO) mice exhibited severe steatosis, inflammation, and injury in the liver. Gene expression analysis and biochemical study revealed that de novo lipogenesis activity was significantly increased in AhR LKO mice. In contrast, induction of suppressor of cytokine signal 3 (Socs3) expression by HFD was attenuated in the livers of AhR LKO mice. Rescue of the Socs3 gene in the liver of AhR LKO mice cancelled the HFD-induced hepatic lipotoxicities. Promoter analysis established Socs3 as novel transcriptional target of AhR. These results indicated that AhR plays a protective role against HFD-induced hepatic steatosis and the subsequent lipotoxicity effects, such as inflammation, and that the mechanism of protection involves the direct transcriptional regulation of Socs3 expression by AhR. PMID:26865635

AhR and Arnt differentially regulate NF-κB signaling and chemokine responses in human bronchial epithelial cells

PubMed Central

2014-01-01

Background The aryl hydrocarbon receptor (AhR) has gradually emerged as a regulator of inflammation in the lung and other tissues. AhR may interact with the p65-subunit of the nuclear factor (NF)-κB transcription factors, but reported outcomes of AhR/NF-κB-interactions are conflicting. Some studies suggest that AhR possess pro-inflammatory activities while others suggest that AhR may be anti-inflammatory. The present study explored the impact of AhR and its binding partner AhR nuclear translocator (Arnt) on p65-activation and two differentially regulated chemokines, CXCL8 (IL-8) and CCL5 (RANTES), in human bronchial epithelial cells (BEAS-2B). Results Cells were exposed to CXCL8- and CCL5-inducing chemicals, 1-nitropyrene (1-NP) and 1-aminopyrene (1-AP) respectively, or the synthetic double-stranded RNA analogue, polyinosinic-polycytidylic acid (Poly I:C) which induced both chemokines. Only CXCL8, and not CCL5, appeared to be p65-dependent. Yet, constitutively active unligated AhR suppressed both CXCL8 and CCL5, as shown by siRNA knock-down and the AhR antagonist α-naphthoflavone. Moreover, AhR suppressed activation of p65 by TNF-α and Poly I:C as assessed by luciferase-assay and p65-phosphorylation at serine 536, without affecting basal p65-activity. In contrast, Arnt suppressed only CXCL8, but did not prevent the p65-activation directly. However, Arnt suppressed expression of the NF-κB-subunit RelB which is under transcriptional regulation by p65. Furthermore, AhR-ligands alone at high concentrations induced a moderate CXCL8-response, without affecting CCL5, but suppressed both CXCL8 and CCL5-responses by Poly I:C. Conclusion AhR and Arnt may differentially and independently regulate chemokine-responses induced by both inhaled pollutants and pulmonary infections. Constitutively active, unligated AhR suppressed the activation of p65, while Arnt may possibly interfere with the action of activated p65. Moreover, ligand-activated AhR suppressed CXCL8 and CCL5

AhR modulates the IL-22-producing cell proliferation/recruitment in imiquimod-induced psoriasis mouse model.

PubMed

Cochez, Perrine M; Michiels, Camille; Hendrickx, Emilie; Van Belle, Astrid B; Lemaire, Muriel M; Dauguet, Nicolas; Warnier, Guy; de Heusch, Magali; Togbe, Dieudonnée; Ryffel, Bernhard; Coulie, Pierre G; Renauld, Jean-Christophe; Dumoutier, Laure

2016-06-01

IL-22 has a detrimental role in skin inflammatory processes, for example in psoriasis. As transcription factor, AhR controls the IL-22 production by several cell types (i.e. Th17 cells). Here, we analyzed the role of Ahr in IL-22 production by immune cells in the inflamed skin, using an imiquimod-induced psoriasis mouse model. Our results indicate that IL-22 is expressed in the ear of imiquimod-treated Ahr(-/-) mice but less than in wild-type mice. We then studied the role of AhR on three cell populations known to produce IL-22 in the skin: γδ T cells, Th17 cells, and ILC3, and a novel IL-22-producing cell type identified in this setting: CD4(-) CD8(-) TCRβ(+) T cells. We showed that AhR is required for IL-22 production by Th17, but not by the three other cell types, in the imiquimod-treated ears. Moreover, AhR has a role in the recruitment of γδ T cells, ILC3, and CD4(-) CD8(-) TCRβ(+) T cells into the inflamed skin or in their local proliferation. Taken together, AhR has a direct role in IL-22 production by Th17 cells in the mouse ear skin, but not by γδ T cells, CD4(-) CD8(-) TCRβ(+) T cells and ILCs. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans.

PubMed

Shinde, Rahul; Hezaveh, Kebria; Halaby, Marie Jo; Kloetgen, Andreas; Chakravarthy, Ankur; da Silva Medina, Tiago; Deol, Reema; Manion, Kieran P; Baglaenko, Yuriy; Eldh, Maria; Lamorte, Sara; Wallace, Drew; Chodisetti, Sathi Babu; Ravishankar, Buvana; Liu, Haiyun; Chaudhary, Kapil; Munn, David H; Tsirigos, Aristotelis; Madaio, Michael; Gabrielsson, Susanne; Touma, Zahi; Wither, Joan; De Carvalho, Daniel D; McGaha, Tracy L

2018-06-01

The transcription factor AhR modulates immunity at multiple levels. Here we report that phagocytes exposed to apoptotic cells exhibited rapid activation of AhR, which drove production of the cytokine IL-10. Activation of AhR was dependent on interactions between apoptotic-cell DNA and the pattern-recognition receptor TLR9 that was required for the prevention of immune responses to DNA and histones in vivo. Moreover, disease progression in mouse systemic lupus erythematosus (SLE) correlated with strength of the AhR signal, and the disease course could be altered by modulation of AhR activity. Deletion of AhR in the myeloid lineage caused systemic autoimmunity in mice, and an enhanced AhR transcriptional signature correlated with disease in patients with SLE. Thus, AhR activity induced by apoptotic cell phagocytes maintains peripheral tolerance.

Is chronic AhR activation by rapidly metabolized ligands safe for the treatment of immune-mediated diseases?

PubMed

Ehrlich, Allison K; Kerkvliet, Nancy I

2017-02-01

There is a long standing perception that AhR ligands are automatically disqualified from pharmaceutical development due to their induction of Cyp1a1 as well as their potential for causing "dioxin-like" toxicities. However, recent discoveries of new AhR ligands with potential therapeutic applications have been reported, inviting reconsideration of this policy. One area of exploration is focused on the activation of AhR to promote the generation of regulatory T cells, which control the intensity and duration of immune responses. Rapidly metabolized AhR ligands (RMAhRLs), which do not bioaccumulate in the same manner as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) have been discovered that induce Tregs and display impressive therapeutic efficacy in a broad range of preclinical models of immune-mediated diseases. Given the promise of these RMAhRLs, is the bias against AhR activators still valid? Can RMAhRLs be given chronically to maintain therapeutic levels of AhR activation without producing the same toxicity profile as dioxin-like compounds? Based on our review of the data, there is little evidence to support the indiscriminate exclusion of AhR activators/Cyp1a1 inducers from early drug developmental pipelines. We also found no evidence that short-term treatment with RMAhRLs produce "dioxin-like toxicity" and, in fact, were well tolerated. However, safety testing of individual RMAhRLs under therapeutic conditions, as performed with all promising new drugs, will be needed to reveal whether or not chronic activation of AhR leads to unacceptable adverse outcomes.

Polycyclic Aromatic Hydrocarbons (PAHs) Mediate Transcriptional Activation of the ATP Binding Cassette Transporter ABCB6 Gene via the Aryl Hydrocarbon Receptor (AhR)*

PubMed Central

Chavan, Hemantkumar; Krishnamurthy, Partha

2012-01-01

Liver is endowed with a mechanism to induce hepatic cytochromes P450 (CYP450s) in response to therapeutic drugs and environmental contaminants, leading to increased detoxification and elimination of the xenobiotics. Each CYP450 is composed of an apoprotein moiety and a heme prosthetic group, which is required for CYP450 activity. Thus, under conditions of CYP450 induction, there is a coordinate increase in heme biosynthesis to compensate for the increased expression of CYP450s. ABCB6, a mitochondrial ATP binding cassette transporter, which regulates coproporphyrinogen transport from the cytoplasm into the mitochondria to complete heme biosynthesis, represents a previously unrecognized rate-limiting step in heme biosynthesis. However, it is not known if exposure to drugs and environmental contaminants induces ABCB6 expression, to assure an adequate and apparently coordinated supply of heme for the generation of functional cytochrome holoprotein. In the present study, we demonstrate that polycyclic aromatic hydrocarbons (PAHs), the widely distributed environmental toxicants shown to induce porphyrin accumulation causing hepatic porphyria, up-regulate ABCB6 expression in both mice and humans. Using siRNA technology and Abcb6 knock-out mice, we demonstrate that PAH-mediated increase in hepatic porphyrins is compromised in the absence of ABCB6. Moreover, in vivo studies in aryl hydrocarbon receptor (AhR) knock-out mice demonstrate that PAH induction of ABCB6 is mediated by AhR. Promoter activation studies combined with electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrate direct interactions between the AhR binding sites in the ABCB6 promoter and the AhR receptor, implicating drug activation mechanisms for ABCB6 similar to those found in inducible cytochrome P450s. These studies are the first to describe direct transcriptional activation of both mouse and human ABCB6 by xenobiotics. PMID:22761424

Estrogenic and AhR activities in dissolved phase and suspended solids from wastewater treatment plants.

PubMed

Dagnino, Sonia; Gomez, Elena; Picot, Bernadette; Cavaillès, Vincent; Casellas, Claude; Balaguer, Patrick; Fenet, Hélène

2010-05-15

The distribution of estrogen receptor (ERalpha) and Aryl Hydrocarbon Receptor (AhR) activities between the dissolved phase and suspended solids were investigated during wastewater treatment. Three wastewater treatment plants with different treatment technologies (waste stabilization ponds (WSPs), trickling filters (TFs) and activated sludge supplemented with a biofilter system (ASB)) were sampled. Estrogenic and AhR activities were detected in both phases in influents and effluents. Estrogenic and AhR activities in wastewater influents ranged from 41.8 to 79 ng/L E(2) Eq. and from 37.9 to 115.5 ng/L TCDD Eq. in the dissolved phase and from 5.5 to 88.6 ng/g E(2) Eq. and from 15 to 700 ng/g TCDD Eq. in the suspended solids. For both activities, WSP showed greater or similar removal efficiency than ASB and both were much more efficient than TF which had the lowest removal efficiency. Moreover, our data indicate that the efficiency of removal of ER and AhR activities from the suspended solid phase was mainly due to removal of suspended solids. Indeed, ER and AhR activities were detected in the effluent suspended solid phase indicating that suspended solids, which are usually not considered in these types of studies, contribute to environmental contamination by endocrine disrupting compounds and should therefore be routinely assessed for a better estimation of the ER and AhR activities released in the environment. Copyright 2010 Elsevier B.V. All rights reserved.

The AhR is involved in the regulation of LoVo cell proliferation through cell cycle-associated proteins.

PubMed

Yin, Jiuheng; Sheng, Baifa; Han, Bin; Pu, Aimin; Yang, Kunqiu; Li, Ping; Wang, Qimeng; Xiao, Weidong; Yang, Hua

2016-05-01

Some ingredients in foods can activate the aryl hydrocarbon receptor (AhR) and arrest cell proliferation. In this study, we hypothesized that 6-formylindolo [3, 2-b] carbazole (FICZ) arrests the cell cycle in LoVo cells (a colon cancer line) through the AhR. The AhR agonist FICZ and the AhR antagonist CH223191 were used to treat LoVo cells. Real-time PCR and Western blot analyses were performed to detect the expression of the AhR, CYP1A1, CDK4, cyclinD1, cyclin E, CDK2, P27, and pRb. The distribution and activation of the AhR were detected with immunofluorescence. A 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometric analysis were performed to measure cell viability, cell cycle stage, and apoptosis. Our results show that FICZ inhibited LoVo cell proliferation by inducing G1 cell cycle arrest but had no effect on epithelial apoptosis. Further analysis found that FICZ downregulated cyclinD1 and upregulated p27 expression to arrest Rb phosphorylation. The downregulation of cyclinD1 and upregulation of p27 were abolished by co-treatment with CH223191. We conclude that the AhR, when activated by FICZ (an endogenous AhR ligand), can arrest the cell cycle and block LoVo cell proliferation. © 2016 International Federation for Cell Biology.

Involvement of the cytokine-IDO1-AhR loop in zinc oxide nanoparticle-induced acute pulmonary inflammation.

PubMed

Ho, Chia-Chi; Lee, Hui-Ling; Chen, Chao-Yu; Luo, Yueh-Hsia; Tsai, Ming-Hsien; Tsai, Hui-Ti; Lin, Pinpin

2017-04-01

Zinc oxide nanoparticles (ZnONPs) are widely used in our daily life, such as in sunscreens and electronic nanodevices. However, pulmonary exposure to ZnONPs causes acute pulmonary inflammation, which is considered as an initial event for various respiratory diseases. Thus, elucidation of the underlying cellular mechanisms of ZnONPs can help us in predicting their potential effects in respiratory diseases. In this study, we observed that ZnONPs increased proinflammatory cytokines, accompanied with an increased expression of aryl hydrocarbon receptor (AhR) and its downstream target cytochrome P450 1A1 (CYP1A1) in macrophages in vitro and in mouse lung epithelia in vivo. Moreover, zinc nitrate, but not silica or titanium dioxide nanoparticles (NPs), had similar effects on macrophages, indicating that the zinc element or ion released from ZnONPs is likely responsible for the activation of the AhR pathway. Cotreatment with an AhR antagonist or AhR knockout reduced ZnONPs-induced cytokine secretion in macrophages or mice, respectively. Furthermore, kynurenine (KYN), an endogenous AhR agonist and a tryptophan metabolite catalyzed by indoleamine 2,3-dioxygenase (IDO), was increased in the serums of mice that aspirated ZnONPs. Consistently, ZnONPs increased IDO1 expression in lung cells in vitro and in vivo. Finally, AhR knockout reduced ZnONPs-induced pulmonary inflammation, cytokine secretion and KYN production in mice, suggesting that AhR activation is involved in ZnONPs-induced cytokine secretion and pulmonary inflammation. In summary, we demonstrated that the pulmonary exposure of ZnONPs stimulated the cytokine-IDO1-AhR loop in the lungs, which has been implied to play roles in immune dysfunctions.

An Assessment of Technical and Production Risks of Candidate Low-Cost Attitude/Heading Reference Systems(AHRS)

NASA Technical Reports Server (NTRS)

Yuchnovicz, Daniel; Burgess, Malcolm; Hammers, William

1999-01-01

This report provides an assessment of technical and production risks of candidate low-cost attitude/heading reference systems (AHRS) for use in the Advanced General Aviation Transport Experiments (AGATE) airplanes. A low-cost AHRS is a key component of modem "glass cockpit" flight displays for General Aviation (GA) aircraft. The technical capabilities of several candidate low-cost AHRS were examined and described along with the technical issues involved with using all solid-state components for attitude measurement. An economic model was developed which describes the expected profit, rate of return, and volume requirements for the manufacture of low-cost AHRS for GA aircraft in the 2000 to 2020 time frame. The model is the result of interviews with GA airframe manufacturers, avionics manufacturers and historical analysis of avionics of similar complexity. The model shows that a manufacturer will break even after three years of AHRS production, realizing an 18 percent rate of return (23 percent profit) on an investment of $3.5M over the 20 year period. A start-up production estimate showed costs of $6-12M for a new company to build and certify an AHRS from scratch, considered to be a high-risk proposition, versus $0.25-0.75M for an experienced avionics manufacturer to manufacture a design under license, a low-risk proposition.

76 FR 80447 - Eighth Meeting: RTCA Special Committee 219: Attitude and Heading Reference Systems (AHRS)

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-23

... Committee 219: Attitude and Heading Reference Systems (AHRS) AGENCY: Federal Aviation Administration (FAA), U.S. Department of Transportation (DOT). ACTION: Notice of RTCA Special Committee 219: Attitude and... eighth meeting of RTCA Special Committee 219: Attitude and Heading Reference Systems (AHRS). DATES: The...

Genomewide Analysis of Aryl Hydrocarbon Receptor Binding Targets Reveals an Extensive Array of Gene Clusters that Control Morphogenetic and Developmental Programs

PubMed Central

Sartor, Maureen A.; Schnekenburger, Michael; Marlowe, Jennifer L.; Reichard, John F.; Wang, Ying; Fan, Yunxia; Ma, Ci; Karyala, Saikumar; Halbleib, Danielle; Liu, Xiangdong; Medvedovic, Mario; Puga, Alvaro

2009-01-01

Background The vertebrate aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates cellular responses to environmental polycyclic and halogenated compounds. The naive receptor is believed to reside in an inactive cytosolic complex that translocates to the nucleus and induces transcription of xenobiotic detoxification genes after activation by ligand. Objectives We conducted an integrative genomewide analysis of AHR gene targets in mouse hepatoma cells and determined whether AHR regulatory functions may take place in the absence of an exogenous ligand. Methods The network of AHR-binding targets in the mouse genome was mapped through a multipronged approach involving chromatin immunoprecipitation/chip and global gene expression signatures. The findings were integrated into a prior functional knowledge base from Gene Ontology, interaction networks, Kyoto Encyclopedia of Genes and Genomes pathways, sequence motif analysis, and literature molecular concepts. Results We found the naive receptor in unstimulated cells bound to an extensive array of gene clusters with functions in regulation of gene expression, differentiation, and pattern specification, connecting multiple morphogenetic and developmental programs. Activation by the ligand displaced the receptor from some of these targets toward sites in the promoters of xenobiotic metabolism genes. Conclusions The vertebrate AHR appears to possess unsuspected regulatory functions that may be potential targets of environmental injury. PMID:19654925

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

PubMed

Kimura, Eiki; Kubo, Ken-Ichiro; Endo, Toshihiro; Nakajima, Kazunori; Kakeyama, Masaki; Tohyama, Chiharu

2017-01-01

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.

T-cell expression of AhR inhibits the maintenance of pTreg cells in the gastrointestinal tract in acute GVHD.

PubMed

Dant, Trisha A; Lin, Kaifeng L; Bruce, Danny W; Montgomery, Stephanie A; Kolupaev, Oleg V; Bommiasamy, Hemamalini; Bixby, Lisa M; Woosley, John T; McKinnon, Karen P; Gonzalez, Frank J; Blazar, Bruce R; Vincent, Benjamin G; Coghill, James M; Serody, Jonathan S

2017-07-20

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that affects the function and development of immune cells. Here, we show that recipient mice receiving AhR -/- T cells have improved survival and decreased acute graft-versus-host disease (aGVHD) in 2 different murine allogeneic bone marrow transplant (BMT) models. We also show that CD4 + T cells lacking AhR demonstrate reduced accumulation in secondary lymphoid tissue because of low levels of proliferation 4 days after BMT. Additionally, we found a significant increase in the quantity of peripherally induced regulatory donor T (pT reg ) cells in the colon of recipients transplanted with AhR -/- T cells 14 days after transplant. Blockade of AhR using a clinically available AhR antagonist greatly enhanced the in vitro generation of inducible T reg (iT reg ) cells from naïve CD4 + human T cells. We have identified AhR as a novel target on donor T cells that is critical to the pathogenesis of aGVHD.

TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells

PubMed Central

Nguyen, Trieu; Iyer, Dharini; Liu, Boxiang; Wang, Ting; Sazonova, Olga; Matic, Ljubica Perisic; Maegdefessel, Lars; Quertermous, Thomas

2017-01-01

Both environmental factors and genetic loci have been associated with coronary artery disease (CAD), however gene-gene and gene-environment interactions that might identify molecular mechanisms of risk are not easily studied by human genetic approaches. We have previously identified the transcription factor TCF21 as the causal CAD gene at 6q23.2 and characterized its downstream transcriptional network that is enriched for CAD GWAS genes. Here we investigate the hypothesis that TCF21 interacts with a downstream target gene, the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates the cellular response to environmental contaminants, including dioxin and polycyclic aromatic hydrocarbons (e.g., tobacco smoke). Perturbation of TCF21 expression in human coronary artery smooth muscle cells (HCASMC) revealed that TCF21 promotes expression of AHR, its heterodimerization partner ARNT, and cooperates with these factors to upregulate a number of inflammatory downstream disease related genes including IL1A, MMP1, and CYP1A1. TCF21 was shown to bind in AHR, ARNT and downstream target gene loci, and co-localization was noted for AHR-ARNT and TCF21 binding sites genome-wide in regions of HCASMC open chromatin. These regions of co-localization were found to be enriched for GWAS signals associated with cardio-metabolic as well as chronic inflammatory disease phenotypes. Finally, we show that similar to TCF21, AHR gene expression is increased in atherosclerotic lesions in mice in vivo using laser capture microdissection, and AHR protein is localized in human carotid atherosclerotic lesions where it is associated with protein kinases with a critical role in innate immune response. These data suggest that TCF21 can cooperate with AHR to activate an inflammatory gene expression program that is exacerbated by environmental stimuli, and may contribute to the overall risk for CAD. PMID:28481916

Malformation of certain brain blood vessels caused by TCDD activation of Ahr2/Arnt1 signaling in developing zebrafish.

PubMed

Teraoka, Hiroki; Ogawa, Akira; Kubota, Akira; Stegeman, John J; Peterson, Richard E; Hiraga, Takeo

2010-08-15

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes various signs of toxicity in early life stages of vertebrates through activation of the aryl hydrocarbon receptor (AHR). The AHR also plays important roles in normal development in mice, and AHR(-/-) mice show abnormal development of vascular structures in various blood vessels. Our previous studies revealed that Ahr type 2 (Ahr2) activation by TCDD and beta-naphthoflavone (BNF) caused a significant decrease in blood flow in the dorsal midbrain of zebrafish embryos. Here we report effects of TCDD exposure on the morphology of some blood vessels in the head of developing zebrafish. TCDD caused concentration-dependent anatomical rearrangements in the shape of the prosencephalic artery in zebrafish larvae. In contrast, no major vascular defects were recognized in the trunk and tail regions following exposure to TCDD at least at the concentrations used. Essentially, the same observations were also confirmed in BNF-exposed larvae. Knock-down of either Ahr2 or Ahr nuclear translocator type 1 (Arnt1) by morpholino oligonucleotides (MOs) protected larvae against abnormal shape of the prosencephalic artery caused by TCDD and BNF. On the other hand, knock-down of Ahr2 or Arnt1 in vehicle-exposed zebrafish larvae had no clear effect on morphology of the prosencephalic artery or trunk vessels. Ascorbic acid, an antioxidant, protected against the TCDD-induced decrease in blood flow through the prosencephalic artery, but not the abnormal morphological changes in the shape of this artery. These results indicate that activation of Ahr2/Arnt1 pathway by TCDD and BNF affects the shape of certain blood vessels in the brain of developing zebrafish. (c) 2010 Elsevier B.V. All rights reserved.

Molecular modeling of the AhR structure and interactions can shed light on ligand-dependent activation and transformation mechanisms.

PubMed

Bonati, Laura; Corrada, Dario; Tagliabue, Sara Giani; Motta, Stefano

2017-02-01

Molecular modeling has given important contributions to elucidation of the main stages in the AhR signal transduction pathway. Despite the lack of experimentally determined structures of the AhR functional domains, information derived from homologous systems has been exploited for modeling their structure and interactions. Homology models of the AhR PASB domain have provided information on the binding cavity and contributed to elucidate species-specific differences in ligand binding. Molecular Docking simulations of the ligand binding process have given insights into differences in binding of diverse agonists, antagonists, and selective AhR modulators, and their application to virtual screening of large databases of compounds have allowed identification of novel AhR ligands. Recently available structural information on protein-protein and protein-DNA complexes of other bHLH-PAS systems has opened the way for modeling the AhR:ARNT dimer structure and investigating the mechanisms of AhR transformation and DNA binding. Future research directions should include simulation of the protein dynamics to obtain a more reliable description of intermolecular interactions involved in signal transmission.

Obesity is mediated by differential aryl hydrocarbon receptor signaling in mice fed a Western diet.

PubMed

Kerley-Hamilton, Joanna S; Trask, Heidi W; Ridley, Christian J A; Dufour, Eric; Ringelberg, Carol S; Nurinova, Nilufer; Wong, Diandra; Moodie, Karen L; Shipman, Samantha L; Moore, Jason H; Korc, Murray; Shworak, Nicholas W; Tomlinson, Craig R

2012-09-01

Obesity is a growing worldwide problem with genetic and environmental causes, and it is an underlying basis for many diseases. Studies have shown that the toxicant-activated aryl hydrocarbon receptor (AHR) may disrupt fat metabolism and contribute to obesity. The AHR is a nuclear receptor/transcription factor that is best known for responding to environmental toxicant exposures to induce a battery of xenobiotic-metabolizing genes. The intent of the work reported here was to test more directly the role of the AHR in obesity and fat metabolism in lieu of exogenous toxicants. We used two congenic mouse models that differ at the Ahr gene and encode AHRs with a 10-fold difference in signaling activity. The two mouse strains were fed either a low-fat (regular) diet or a high-fat (Western) diet. The Western diet differentially affected body size, body fat:body mass ratios, liver size and liver metabolism, and liver mRNA and miRNA profiles. The regular diet had no significant differential effects. The results suggest that the AHR plays a large and broad role in obesity and associated complications, and importantly, may provide a simple and effective therapeutic strategy to combat obesity, heart disease, and other obesity-associated illnesses.

Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mahiout, Selma, E-mail: selma.mahiout@helsinki.fi

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 highestmore » 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. - Highlights

The AhR and NF-κB/Rel Proteins Mediate the Inhibitory Effect of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on the 3′ Immunoglobulin Heavy Chain Regulatory Region

PubMed Central

Salisbury, Richard L.; Sulentic, Courtney E. W.

2015-01-01

Transcriptional regulation of the murine immunoglobulin (Ig) heavy chain gene (Igh) involves several regulatory elements including the 3′Igh regulatory region (3′IghRR), which is composed of at least 4 enhancers (hs3A, hs1.2, hs3B, and hs4). The hs1.2 and hs4 enhancers exhibit the greatest transcriptional activity and contain binding sites for several transcription factors including nuclear factor kappaB/Rel (NF-κB/Rel) proteins and the aryl hydrocarbon receptor (AhR). Interestingly, the environmental immunosuppressant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which potently inhibits antibody secretion, also profoundly inhibits 3′IghRR and hs1.2 enhancer activation induced by the B-lymphocyte activator lipopolysaccharide (LPS), but enhances LPS-induced activation of the hs4 enhancer. Within the hs1.2 and hs4 enhancers, the AhR binding site is in close proximity or overlaps an NF-κB/Rel binding site suggesting a potential reciprocal modulation of the 3′IghRR by AhR and NF-κB/Rel. The objective of the current study was to evaluate the role of NF-κB/Rel and the AhR on the 3′IghRR and its enhancers using the AhR ligand TCDD, the AhR antagonist CH223191, and toll-like receptor agonists LPS, Resiquimod (R848), or cytosine-phosphate-guanine-oligodeoxynucleotides (CpG). Utilizing the CH12.LX B-lymphocyte cell line and variants expressing either a 3′IghRR-regulated transgene reporter or an inducible IκBα (inhibitor kappa B-alpha protein) superrepressor (IκBαAA), we demonstrate an AhR- and NF-κB/Rel-dependent modulation of 3′IghRR and hs4 activity. Additionally, in mouse splenocytes or CH12.LX cells, binding within the hs1.2 and hs4 enhancer of the AhR and the NF-κB/Rel proteins RelA and RelB was differentially altered by the cotreatment of LPS and TCDD. These results suggest that the AhR and NF-κB/Rel protein binding profile within the 3′IghRR mediates the inhibitory effects of TCDD on Ig expression and therefore antibody levels. PMID:26377645

Induction of AhR-Mediated Gene Transcription by Coffee

PubMed Central

Ishikawa, Toshio; Takahashi, Satoshi; Morita, Koji; Okinaga, Hiroko; Teramoto, Tamio

2014-01-01

Background Aryl hydrocarbon receptor (AhR) is classically known to be activated by xenobiotics such as dioxins and polycyclic aromatic hydrocarbons (PAHs). Although it has been reported that PAHs are contained in roasted coffee beans, in general coffee beverages are not considered to be AhR activators. We tested whether exposure to coffee would activate AhR in cultured cells. Methods HepG2 cells stably expressing an AhR-responsive reporter gene were treated with coffee samples. Also, expression of CYP1A1, an endogenous AhR-responsive gene, was quantitated by RT-PCR and Western blotting in HepG2, Caco-2, and MCF-7 cells, after treatment with coffee. In order to obtain sensitive and reproducible results, all the experiments were performed with the cells placed in either phosphate-buffered saline (PBS) or pure serum, instead of routinely-used culture medium, whose intrinsic AhR-stimulating activity turned out to be so strong as to interfere with the analyses. Results All the coffee samples tested robustly stimulated AhR-mediated transcription in the reporter gene assays. Of note, to what extent coffee and other AhR agonists activated AhR was different, depending on whether the experiments were done in PBS or serum. CYP1A1 mRNA was induced by coffee, in HepG2, Caco-2, and MCF-7 cells placed in either PBS or serum. CYP1A1 protein expression, which was not detected in these cells incubated in PBS, was also increased by coffee in cells placed in serum. Conclusions By using culture medium-free experimental settings, we have shown that coffee is a strong AhR activator. Our observation may help elucidate as-yet-unrecognized effects of coffee on human health. PMID:25007155

Binding Mode and Structure-Activity Relationships of ITE as an Aryl Hydrocarbon Receptor (AhR) Agonist.

PubMed

Dolciami, Daniela; Gargaro, Marco; Cerra, Bruno; Scalisi, Giulia; Bagnoli, Luana; Servillo, Giuseppe; Fazia, Maria Agnese Della; Puccetti, Paolo; Quintana, Francisco J; Fallarino, Francesca; Macchiarulo, Antonio

2018-02-06

Discovered as a modulator of the toxic response to environmental pollutants, aryl hydrocarbon receptor (AhR) has recently gained attention for its involvement in various physiological and pathological pathways. AhR is a ligand-dependent transcription factor activated by a large array of chemical compounds, which include metabolites of l-tryptophan (l-Trp) catabolism as endogenous ligands of the receptor. Among these, 2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester (ITE) has attracted interest in the scientific community, being endowed with nontoxic, immunomodulatory, and anticancer AhR-mediated functions. So far, no information about the binding mode and interactions of ITE with AhR is available. In this study, we used docking and molecular dynamics to propose a putative binding mode of ITE into the ligand binding pocket of AhR. Mutagenesis studies were then instrumental in validating the proposed binding mode, identifying His 285 and Tyr 316 as important key residues for ligand-dependent receptor activation. Finally, a set of ITE analogues was synthesized and tested to further probe molecular interactions of ITE to AhR and characterize the relevance of specific functional groups in the chemical structure for receptor activity. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Immunological characterization of the aryl hydrocarbon receptor (AHR) knockout rat in the presence and absence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

PubMed

Phadnis-Moghe, Ashwini S; Chen, Weimin; Li, Jinpeng; Crawford, Robert B; Bach, Anthony; D'Ingillo, Shawna; Kovalova, Natalia; Suarez-Martinez, Jose E; Kaplan, Barbara L F; Harrill, Joshua A; Budinsky, Robert; Rowlands, J Craig; Thomas, Russell S; Kaminski, Norbert E

2016-08-10

The aryl hydrocarbon receptor (AHR) has been extensively characterized for the essential role it plays in mediating the toxic responses elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Despite similarities across animal species, species-specific differences exist in the profile of toxicity and sensitivity to TCDD owing, in part, to differences in the AHR. Newer reports have implicated the importance of AHR in the development and regulation of the immune system. Our present studies seek to further explore the essential role of AHR in lymphoid tissue composition, B cell function and the immunological responses after TCDD administration using the recently established AHR KO rats. Comprehensive immune cell phenotyping showed a decrease in the CD8 + T cell, CD11c + populations and an increase in NKT cells in 3-week-old AHR KO rats compared to the WT controls. The lipopolysaccharide-induced IgM response and proliferation was markedly suppressed in the WT but not in the AHR KO B cells in the presence of TCDD. However, the percentage of LPS-activated IgM + B cells was significantly higher in the AHR KO B cells as compared to that of WT suggesting the role of AHR in regulating the IgM response. The use of an AHR antagonist further alluded to the endogenous role of AHR in regulating B cell responses in the rat. Overall, the studies report for the first time, comprehensive immune cell phenotyping of the AHR KO rat and the endogenous role of AHR in the regulation of B cell function in the rat. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Lithium Ion Testing at NSWC Crane in Support of NASA Goddard Space Flight Center

NASA Technical Reports Server (NTRS)

Brown, Harry; Jung, David; Lee, Leonine

2010-01-01

This viewgraph presentation reviews Lithium Ion Cell testing at the Naval Surface Warfare Center in Crane, India. The contents include: 1) Quallion 15 Ahr Lithium-Ion Cells, LEO Life Cycle Test; 2) Lithion 50 Ahr Lithium-Ion Cells, LEO Life Cycle Test; 3) ABSL 5 Ahr Lithium-Ion Battery, LRO-LLO Life Cycle Test, SDO-GEO Life Cycle Test; and 4) A123 40 Ahr Lithium-Ion Battery, GPM Life Cycle Test, MMS Life Cycle Test.

Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area.

PubMed

Girolami, Flavia; Spalenza, Veronica; Carletti, Monica; Sacchi, Paola; Rasero, Roberto; Nebbia, Carlo

2013-04-15

Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. Copyright © 2013 Elsevier B.V. All rights reserved.

Examination of Zolpidem effects on AhR- and PXR-dependent expression of drug-metabolizing cytochromes P450 in primary cultures of human hepatocytes.

PubMed

Bachleda, Petr; Vrzal, Radim; Pivnicka, Jakub; Cvek, Boris; Dvorak, Zdenek

2009-12-01

A hypnotic drug Zolpidem is used in clinical practice for more than 25 years. Surprisingly, the effects of Zolpidem on the expression of drug-metabolizing cytochromes P450 (CYPs) were not examined yet. Recently, the unexpected capacity of several "old drugs", such as valproic acid or azoles, to induce CYPs was reported. Therefore, we tested whether Zolpidem induces the expression of important CYPs in primary cultures of human hepatocytes. Cells were treated for 24h with Zolpidem in therapeutic (0.1mg/L) and toxic (1mg/L) concentrations. The levels of CYP1A1, CYP1A2, CY2C9 and CYP3A4 mRNAs were not altered by Zolpidem, whereas model inducers dioxin and rifampicin significantly induced CYP1A and CYP2/3 gene expression, respectively. Consistently, Zolpidem did not activate aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR), the key regulators of cytochromes P450s, as revealed by transient transfection gene reporter assays using HepG2 cells. We conclude Zolpidem be considered a safe drug with respect to the possible interactions through AhR- and PXR-dependent induction of drug-metabolizing CYPs.

Detection of Aryl Hydrocarbon Receptor Activation by Some Chemicals in Food Using a Reporter Gene Assay

PubMed Central

Amakura, Yoshiaki; Tsutsumi, Tomoaki; Yoshimura, Morio; Nakamura, Masafumi; Handa, Hiroshi; Matsuda, Rieko; Teshima, Reiko; Watanabe, Takahiro

2016-01-01

The purpose of this study was to examine whether a simple bioassay used for the detection of dioxins (DXNs) could be applied to detect trace amounts of harmful DXN-like substances in food products. To identify substances with possible DXN-like activity, we assessed the ability of various compounds in the environment to bind the aryl hydrocarbon receptor (AhR) that binds specifically to DXNs. The compounds tested included 19 polycyclic aromatic hydrocarbons (PAHs), 20 PAH derivatives (nitrated, halogenated, and aminated derivatives), 23 pesticides, six amino acids, and eight amino acid metabolites. The AhR binding activities (AhR activity) of these compounds were measured using the chemical activated luciferase gene expression (CALUX) reporter gene assay system. The majority of the PAHs exhibited marked AhR activity that increased in a concentration-dependent manner. Furthermore, there was a positive link between AhR activity and the number of aromatic rings in the PAH derivatives. Conversely, there appeared to be a negative correlation between AhR activity and the number of chlorine residues present on halogenated PAH derivatives. However, there was no correlation between AhR activity and the number and position of substituents among nitrated and aminated derivatives. Among the pesticides tested, the indole-type compounds carbendazim and thiabendazole showed high levels of activity. Similarly, the indole compound tryptamine was the only amino acid metabolite to induce AhR activity. The results are useful in understanding the identification and characterization of AhR ligands in the CALUX assay. PMID:28231110

Ablating the aryl hydrocarbon receptor (AhR) in CD11c+ cells perturbs intestinal epithelium development and intestinal immunity.

PubMed

Chng, Song Hui; Kundu, Parag; Dominguez-Brauer, Carmen; Teo, Wei Ling; Kawajiri, Kaname; Fujii-Kuriyama, Yoshiaki; Mak, Tak Wah; Pettersson, Sven

2016-04-12

Diet and microbiome derived indole derivatives are known to activate the ligand induced transcription factor, the Aryl hydrocarbon Receptor (AhR). While the current understanding of AhR biology has confirmed its role in mucosal lymphocytes, its function in intestinal antigen presenting cells (APCs) is poorly understood. Here, we report that Cre-mediated deletion of AhR in CD11c-expressing cells in C57/BL6 mice is associated with altered intestinal epithelial morphogenesis in vivo. Moreover, when co-cultured with AhR-deficient DCs ex vivo, intestinal organoids showed reduced SRY (sex determining region Y)-box 9 and increased Mucin 2 expression, which correlates with reduced Paneth cells and increased goblet cell differentiation, similar to the data obtained in vivo. Further, characterization of intestinal APC subsets, devoid of AhR, revealed an expression pattern associated with aberrant intrinsic Wnt pathway regulation. At a functional level, the loss of AhR in APCs resulted in a dysfunctional epithelial barrier, associated with a more aggressive chemically induced colitis compared to wild type animals. Our results are consistent with a model whereby the AhR signalling pathway may participate in the regulation of innate immunity through intestinal epithelium development and mucosal immunity.

Lymphocyte-specific protein tyrosine kinase (LCK) is involved in the aryl hydrocarbon receptor (AHR)-mediated impairment of immunoglobulin secretion in human primary B cells.

PubMed

Zhou, Jiajun; Zhang, Qiang; Henriquez, Joseph E; Crawford, Robert B; Kaminski, Norbert E

2018-05-31

The aryl hydrocarbon receptor (AHR) is a cytosolic ligand-activated transcription factor involved in xenobiotic sensing, cell cycle regulation and cell development. In humans, the activation of AHR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a high affinity AHR-ligand, impairs the secretion of immunoglobulin M (IgM) to suppress humoral immunity. However, the mechanisms bridging the activation of AHR and the impairment of IgM secretion by human primary B cells remain poorly understood. Recent transcriptomic analysis revealed upregulation of lymphocyte-specific protein tyrosine kinase (LCK) in AHR activated human primary B cells. LCK is a well-characterized tyrosine kinase that phosphorylates critical signaling proteins involved in activation and cytokine production in T cells. Conversely, the role of LCK in human primary B cells is not well understood. In the current studies, we have verified the transcriptomic finding by detecting AHR-mediated upregulation of LCK protein in human primary B cells. We also confirmed the role of AHR in the upregulation of LCK by using a specific AHR antagonist, which abolished the AHR-mediated increase of LCK. Furthermore, we have confirmed the role of LCK in the AHR-mediated suppression of IgM by using LCK specific inhibitors, which restored IgM secretion by human B cells in the presence of TCDD. Collectively, the current studies demonstrate a novel role of LCK in IgM secretion and provide new insights into the mechanism for AHR-mediated impairment of immunoglobulin secretion by human primary B cells.

Structure of the C-terminal effector-binding domain of AhrC bound to its corepressor l-arginine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garnett, James A.; Baumberg, Simon; Stockley, Peter G.

2007-11-01

The crystal structure of the C-terminal domain hexameric core of AhrC, with bound corepressor (l-arginine), has been solved at 1.95 Å resolution. Binding of l-arginine results in a rotation between the two trimers of the hexamer, leading to the activation of the DNA-binding state. The arginine repressor/activator protein (AhrC) from Bacillus subtilis belongs to a large family of multifunctional transcription factors that are involved in the regulation of bacterial arginine metabolism. AhrC interacts with operator sites in the promoters of arginine biosynthetic and catabolic operons, acting as a transcriptional repressor at biosynthetic sites and an activator of transcription at catabolicmore » sites. AhrC is a hexamer of identical subunits, each having two domains. The C-terminal domains form the core of the protein and are involved in oligomerization and l-arginine binding. The N-terminal domains lie on the outside of the compact core and play a role in binding to 18 bp DNA operators called ARG boxes. The C-terminal domain of AhrC has been expressed, purified and characterized, and also crystallized as a hexamer with the bound corepressor l-arginine. Here, the crystal structure refined to 1.95 Å is presented.« less

The Role of AhR in Autoimmune Regulation and Its Potential as a Therapeutic Target against CD4 T Cell Mediated Inflammatory Disorder

PubMed Central

Zhu, Conghui; Xie, Qunhui; Zhao, Bin

2014-01-01

AhR has recently emerged as a critical physiological regulator of immune responses affecting both innate and adaptive systems. Since the AhR signaling pathway represents an important link between environmental stimulators and immune-mediated inflammatory disorder, it has become the object of great interest among researchers recently. The current review discusses new insights into the mechanisms of action of a select group of inflammatory autoimmune diseases and the ligand-activated AhR signaling pathway. Representative ligands of AhR, both exogenous and endogenous, are also reviewed relative to their potential use as tools for understanding the role of AhR and as potential therapeutics for the treatment of various inflammatory autoimmune diseases, with a focus on CD4 helper T cells, which play important roles both in self-immune tolerance and in inflammatory autoimmune diseases. Evidence indicating the potential use of these ligands in regulating inflammation in various diseases is highlighted, and potential mechanisms of action causing immune system effects mediated by AhR signaling are also discussed. The current review will contribute to a better understanding of the role of AhR and its signaling pathway in CD4 helper T cell mediated inflammatory disorder. Considering the established importance of AhR in immune regulation and its potential as a therapeutic target, we also think that both further investigation into the molecular mechanisms of immune regulation that are mediated by the ligand-specific AhR signaling pathway, and integrated research and development of new therapeutic drug candidates targeting the AhR signaling pathway should be pursued urgently. PMID:24905409

[Association between aryl hydrocarbon receptor gene polymorphisms and chromosomal damage in coke-oven workers].

PubMed

Bin, Ping; Leng, Shuguang; Liang, Xuemiao; Cheng, Juan

2007-11-01

To investigate the association of single nucleotide polymorphisms (SNPs) or haplotypes of aryl hydrocarbon receptor (AHR) gene and chromosomal damage in peripheral blood lymphocytes among coke-oven workers. Eighty-nine coke-oven workers exposed to a high level of polycyclic aromatic hydrocarbons (PAHs) and sixty non-exposed workers were selected as the study subjects. Urinary 1-hydroxypyrene (1-OHPyr) levels were measured as the internal dose of PAHs exposure. The chromosomal damage in peripheral lymphocyte was measured by the cytokinesis-block micronucleus (CBMN) assay. Two SNPs in AHR gene, including rs6960165, rs2282885 were detected by PCR-RFLP. The AHR haplotypes were estimated by Bayesian statistical method with the software of PHASE Version 2.1. The associations between SNPs or haplotypes pairs and CBMN were assessed by analysis of covariance in the coke-oven workers and non-exposed workers. The level of 1-OHPyr among coke-oven workers was significantly higher than that among non-exposed workers (P < 0.01). The CBMN among coke-oven workers was significantly higher than that among non-exposed workers (P < 0.01). After adjusting the age and the level of 1-OHPyr, the different SNPs of AHR gene rs6960165 in coke-oven workers were related to the CBMN frequencies (P = 0.014), but no association between the different SNPs of AHR gene rs2282885 and the rates of CBMN was observed in coke-oven workers (P = 0.586), either in the controls (P = 0.308 and P = 0.415, respectively), the haplotypes in coke-oven workers were significantly related to the rates of CBMN (P = 0.007), while there was no significant association in non-exposed workers (P = 0.768). Our results suggested that SNPs rs6960165 or haplotypes of AHR were associated with the CBMN frequencies in coke-oven workers.

TCDD, FICZ, and Other High Affinity AhR Ligands Dose-Dependently Determine the Fate of CD4+ T Cell Differentiation.

PubMed

Ehrlich, Allison K; Pennington, Jamie M; Bisson, William H; Kolluri, Siva K; Kerkvliet, Nancy I

2018-02-01

FICZ and TCDD, two high-affinity AhR ligands, are reported to have opposite effects on T cell differentiation with TCDD inducing regulatory T cells and FICZ inducing Th17 cells. This dichotomy has been attributed to ligand-intrinsic differences in AhR activation, although differences in sensitivity to metabolism complicate the issue. TCDD is resistant to AhR-induced metabolism and produces sustained AhR activation following a single dose in the μg/kg range, whereas FICZ is rapidly metabolized and AhR activation is transient. Nonetheless, prior studies comparing FICZ with TCDD have generally used the same 10-50 μg/kg dose range, and thus the two ligands would not equivalently activate AhR. We hypothesized that high-affinity AhR ligands can promote CD4+ T cell differentiation into both Th17 cells and Tregs, with fate depending on the extent and duration of AhR activation. We compared the immunosuppressive effects of TCDD and FICZ, along with two other rapidly metabolized ligands (ITE and 11-Cl-BBQ) in an acute alloresponse mouse model. The dose and timing of administration of each ligand was optimized for TCDD-equivalent Cyp1a1 induction. When optimized, all of the ligands suppressed the alloresponse in conjunction with the induction of Foxp3- Tr1 cells on day 2 and the expansion of natural Foxp3+ Tregs on day 10. In contrast, a low dose of FICZ induced transient expression of Cyp1a1 and did not induce Tregs or suppress the alloresponse but enhanced IL-17 production. Interestingly, low doses of the other ligands, including TCDD, also increased IL-17 production on day 10. These findings support the conclusion that the dose and the duration of AhR activation by high-affinity AhR ligands are the primary factors driving the fate of T cell differentiation. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lund, Amie K.; Goens, M. Beth; Nunez, Bethany A.

2006-04-15

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of AhR results in hypertension, and cardiac hypertrophy and fibrosis, associated with elevated plasma angiotensin II (Ang II) and endothelin-1 (ET-1), thus AhR appears to contribute to cardiovascular homeostasis. In these studies, we tested the hypothesis that ET-1 mediates cardiovascular pathology in AhR null mice via ET{sub A} receptor activation. First, we determine the time courses of cardiac hypertrophy, and of plasma and tissue ET-1 expression in AhR wildtype and null mice. AhR null mice exhibitedmore » increases in heart-to-body weight ratio and age-related expression of cardiac hypertrophy markers, {beta}-myosin heavy chain ({beta}-MHC), and atrial natriuretic factor (ANF), which were significant at 2 months. Similarly, plasma and tissue ET-1 expression was significantly elevated at 2 months and increased further with age. Second, AhR null mice were treated with ET{sub A} receptor antagonist, BQ-123 (100 nmol/kg/day), for 7, 28, or 58 days and blood pressure, cardiac fibrosis, and cardiac hypertrophy assessed, respectively. BQ-123 for 7 days significantly reduced mean arterial pressure in conscious, catheterized mice. BQ-123 for 28 days significantly reduced the histological appearance of cardiac fibrosis. Treatment for 58 days significantly reduced cardiac mass, assessed by heart weight, echocardiography, and {beta}-MHC and ANF expression; and reduced cardiac fibrosis as determined by osteopontin and collagen I mRNA expression. These findings establish ET-1 and the ET{sub A} receptor as primary determinants of hypertension and cardiac pathology in AhR null mice.« less

Crimson Viper 2015

DTIC Science & Technology

2015-08-01

lithium charged battery in order to charge batteries Lessons Learned Technology Focused • Don’t wait until execution time to start unit. Even if...communications • Optional passport MRZ and smartcard readers • Dual hot-swappable batteries , 2.4 Ahr, Li Ion , with Smart Battery technology...6.2” x 1.8” (24.13 cm x 15.75 cm x 4.57 cm) Weight 3.2 lbs (1.45 kg) Battery Dual hot-swappable, 2.9 Ahr, Li Ion Battery Life Up to 8 hours

Antioxidant Opuntia ficus-indica Extract Activates AHR-NRF2 Signaling and Upregulates Filaggrin and Loricrin Expression in Human Keratinocytes.

PubMed

Nakahara, Takeshi; Mitoma, Chikage; Hashimoto-Hachiya, Akiko; Takahara, Masakazu; Tsuji, Gaku; Uchi, Hiroshi; Yan, Xianghong; Hachisuka, Junichi; Chiba, Takahito; Esaki, Hitokazu; Kido-Nakahara, Makiko; Furue, Masutaka

2015-10-01

Opuntia ficus-indica (OFI) is a cactus species widely used as an anti-inflammatory, antilipidemic, and hypoglycemic agent. It has been shown that OFI extract (OFIE) inhibits oxidative stress in animal models of diabetes and hepatic disease; however, its antioxidant mechanism remains largely unknown. In this study, we demonstrated that OFIE exhibited potent antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the downstream antioxidant enzyme quinone oxidoreductase 1 (NQO1), which inhibited the generation of reactive oxygen species in keratinocytes challenged with tumor necrosis factor α or benzo[α]pyrene. The antioxidant capacity of OFIE was canceled in NRF2 knockdown keratinocytes. OFIE exerted this NRF2-NQO1 upregulation through activation of the aryl hydrocarbon receptor (AHR). Moreover, the ligation of AHR by OFIE upregulated the expression of epidermal barrier proteins: filaggrin and loricrin. OFIE also prevented TH2 cytokine-mediated downregulation of filaggrin and loricrin expression in an AHR-dependent manner because it was canceled in AHR knockdown keratinocytes. Antioxidant OFIE is a potent activator of AHR-NRF2-NQO1 signaling and may be beneficial in treating barrier-disrupted skin disorders.

Deletion of Aryl Hydrocarbon Receptor AHR in Mice Leads to Subretinal Accumulation of Microglia and RPE Atrophy

PubMed Central

Kim, Soo-Young; Yang, Hyun-Jin; Chang, Yi-Sheng; Kim, Jung-Woong; Brooks, Matthew; Chew, Emily Y.; Wong, Wai T.; Fariss, Robert N.; Rachel, Rivka A.; Cogliati, Tiziana; Qian, Haohua; Swaroop, Anand

2014-01-01

Purpose. The aryl hydrocarbon receptor (AHR) is a ligand-activated nuclear receptor that regulates cellular response to environmental signals, including UV and blue wavelength light. This study was undertaken to elucidate AHR function in retinal homeostasis. Methods. RNA-seq data sets were examined for Ahr expression in the mouse retina and rod photoreceptors. The Ahr−/− mice were evaluated by fundus imaging, optical coherence tomography, histology, immunohistochemistry, and ERG. For light damage experiments, adult mice were exposed to 14,000 to 15,000 lux of diffuse white light for 2 hours. Results. In mouse retina, Ahr transcripts were upregulated during development, with continued increase in aging rod photoreceptors. Fundus examination of 3-month-old Ahr−/− mice revealed subretinal autofluorescent spots, which increased in number with age and following acute light exposure. Ahr−/− retina also showed subretinal microglia accumulation that correlated with autofluorescence changes, RPE abnormalities, and reactivity against immunoglobulin, complement factor H, and glial fibrillary acidic protein. Functionally, Ahr−/− mice displayed reduced ERG c-wave amplitudes. Conclusions. The Ahr−/− mice exhibited subretinal accumulation of microglia and focal RPE atrophy, phenotypes observed in AMD. Together with a recently published report on another Ahr−/− mouse model, our study suggests that AHR has a protective role in the retina as an environmental stress sensor. As such, its altered function may contribute to human AMD progression and provide a target for pharmacological intervention. PMID:25159211

Association of aryl hydrocarbon receptor gene polymorphism with the neurobehavioral function and autonomic nervous system function changes induced by benzo[a]pyrene exposure in coke oven workers.

PubMed

Zhang, Hongmei; Nie, Jisheng; Li, Xin; Niu, Qiao

2013-03-01

To analyze the association of aryl hydrocarbon receptor (AhR) gene polymorphism and the neurotoxicity induced by benzo[a]pyrene (B[a]P) in coke oven workers. Subjects, 214 coke oven workers and 81 controls, were detected for neurobehavioral function and autonomic nervous system (ANS) function. Airborne B[a]P concentration, urinary 1-hydroxypyrene level, and AhR gene polymorphisms were determined and analyzed for their association with B[a]P neurotoxicity. Neurobehavioral function and ANS function were significantly decreased and dependent on B[a]P dose. The AhR GG, GA, and AA genotypes in G1661A fitted the Hardy-Weinberg equation, whereas C1549T and G1708A gene mutants were not detected. Indices indicating neurotoxicity showed no significant difference among individuals with AA, GG, or GA genotype except for the confusion-bewilderment (P > 0.05). The AhR gene polymorphism is not thought to correlate with B[a]P neurotoxicity among coke oven workers.

Identification of the Aryl Hydrocarbon Receptor Target Gene TiPARP as a Mediator of Suppression of Hepatic Gluconeogenesis by 2,3,7,8-Tetrachlorodibenzo-p-dioxin and of Nicotinamide as a Corrective Agent for This Effect*

PubMed Central

Diani-Moore, Silvia; Ram, Payal; Li, Xintian; Mondal, Prosenjit; Youn, Dou Yeon; Sauve, Anthony A.; Rifkind, Arleen B.

2010-01-01

The environmental toxin TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, dioxin) produces diverse toxic effects including a lethal wasting syndrome whose hallmark is suppressed hepatic gluconeogenesis. All TCDD toxicities require activation of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor. Whereas the mechanism for AHR induction of target genes is well understood, it is not known how AHR activation produces any TCDD toxicity. This report identifies for the first time an AHR target gene, TiPARP (TCDD-inducible poly(ADP-ribose) polymerase, PARP7) that can mediate a TCDD toxicity, i.e. suppression of hepatic gluconeogenesis. TCDD suppressed hepatic glucose production, expression of key gluconeogenic genes, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase), and NAD+ levels, and increased PARP activity and TiPARP expression. TCDD also increased acetylation and ubiquitin-dependent proteosomal degradation of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α), a coactivator of PEPCK and G6Pase transcription. TiPARP overexpression reproduced TCDD effects on glucose output and NAD+ levels whereas TiPARP silencing diminished them. TiPARP overexpression also increased PGC1α acetylation and decreased PGC1α levels. In contrast, silencing of cytochromes P450 (CYP) 1A, main AHR-induced genes, did not alter TCDD suppression of gluconeogenesis. The vitamin B3 constituent, nicotinamide (NAM), prevented TCDD suppression of glucose output, NAD+, and gluconeogenic genes and stabilized PGC1α. The corrective effects of NAM could be attributed to increased NAD+ levels and suppression of AHR target gene induction. The results reveal that TiPARP can mediate a TCDD effect, that the AHR is linked to PGC1α function and stability and that NAM has novel AHR antagonist activity. PMID:20876576

Novel roles for AhR and ARNT in the regulation of alcohol dehydrogenases in human hepatic cells.

PubMed

Attignon, Eléonore A; Leblanc, Alix F; Le-Grand, Béatrice; Duval, Caroline; Aggerbeck, Martine; Rouach, Hélène; Blanc, Etienne B

2017-01-01

The mechanisms by which pollutants participate in the development of diverse pathologies are not completely understood. The pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates the AhR (aryl hydrocarbon receptor) signaling pathway. We previously showed that TCDD (25 nM, 30 h) decreased the expression of several alcohol metabolism enzymes (cytochrome P450 2E1, alcohol dehydrogenases ADH1, 4 and 6) in differentiated human hepatic cells (HepaRG). Here, we show that, as rapidly as 8 h after treatment (25 nM TCDD) ADH expression decreased 40 % (p < 0.05). ADH1 and 4 protein levels decreased 40 and 27 %, respectively (p < 0.05), after 72 h (25 nM TCDD). The protein half-lives were not modified by TCDD which suggests transcriptional regulation of expression. The AhR antagonist CH-223191 or AhR siRNA reduced the inhibitory effect of 25 nM TCDD on ADH1A, 4 and 6 expression 50-100 % (p < 0.05). The genomic pathway (via the AhR/ARNT complex) and not the non-genomic pathway involving c-SRC mediated these effects. Other AhR ligands (3-methylcholanthrene and PCB 126) decreased ADH1B, 4 and 6 mRNAs by more than 78 and 55 %, respectively (p < 0.01). TCDD also regulated the expression of ADH4 in the HepG2 human hepatic cell line, in primary human hepatocytes and in C57BL/6J mouse liver. In conclusion, activation of the AhR/ARNT signaling pathway by AhR ligands represents a novel mechanism for regulating the expression of ADHs. These effects may be implicated in the toxicity of AhR ligands as well as in the alteration of ethanol or retinol metabolism and may be associated further with higher risk of liver diseases or/and alcohol abuse disorders.

Plant polyphenols differentially modulate inflammatory responses of human keratinocytes by interfering with activation of transcription factors NF{kappa}B and AhR and EGFR-ERK pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Potapovich, Alla I.; Biology Department, Belarus State University, Skorina Prosp. 10, Minsk 220050; Lulli, Daniela

Molecular mechanisms underlying modulation of inflammatory responses in primary human keratinocytes by plant polyphenols (PPs), namely the glycosylated phenylpropanoid verbascoside, the stilbenoid resveratrol and its glycoside polydatin, and the flavonoid quercetin and its glycoside rutin were evaluated. As non-lethal stimuli, the prototypic ligand for epidermal growth factor receptor (EGFR) transforming growth factor alpha (TGFalpha), the combination of tumor necrosis factor (TNFalpha) and interferon (IFNgamma) (T/I), UVA + UVB irradiation, and bacterial lipopolysaccharide (LPS) were used. We demonstrated differential modulation of inflammatory responses in keratinocytes at signal transduction, gene transcription, and protein synthesis levels as a function of PP chemical structure,more » the pro-inflammatory trigger used, and PP interaction with intracellular detoxifying systems. The PPs remarkably inhibited constitutive, LPS- and T/I-induced but not TGFalpha-induced ERK phosphorylation. They also suppressed NFkappaB activation by LPS and T/I. Verbascoside and quercetin invariably impaired EGFR phosphorylation and UV-associated aryl hydrocarbon receptor (AhR)-mediated signaling, while rutin, polydatin and resveratrol did not affect EGFR phosphorylation and further activated AhR machinery in UV-exposed keratinocytes. In general, PPs down-regulated gene expression of pro-inflammatory cytokines/enzymes, except significant up-regulation of IL-8 observed under stimulation with TGFalpha. Both spontaneous and T/I-induced release of IL-8 and IP-10 was suppressed, although 50 {mu}M resveratrol and polydatin up-regulated IL-8. At this concentration, resveratrol activated both gene expression and de novo synthesis of IL-8 and AhR-mediated mechanisms were involved. We conclude that PPs differentially modulate the inflammatory response of human keratinocytes through distinct signal transduction pathways, including AhR and EGFR. - Graphical abstract: Display Omitted

AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barrett, R.J.; Appell, K.C.; Kilpatrick, B.F.

1991-01-01

In vivo and in vitro methods were used to characterize AHR-16303B, a novel compound with antagonistic action at 5-HT2 receptors and voltage-sensitive calcium channels. The 5-HT2 receptor-antagonistic properties of AHR-16303B were demonstrated by inhibition of (a) (3H)ketanserin binding to rat cerebral cortical membranes (IC50 = 165 nM); (b) 5-hydroxytryptamine (5-HT)-induced foot edema in rats (minimum effective dose, (MED) = 0.32 mg/kg orally, p.o.); (c) 5-HT-induced vasopressor responses in spontaneously hypertensive rats (SHR) (ID50 = 0.18 mg/kg intravenously (i.v.), 1.8 mg/kg p.o.), (d) 5-HT-induced antidiuresis in rats (MED = 1 mg/kg p.o.), and (e) platelet aggregation induced by 5-HT + ADPmore » (IC50 = 1.5 mM). The calcium antagonist properties of AHR-16303B were demonstrated by inhibition of (a) (3H)nimodipine binding to voltage-sensitive calcium channels on rabbit skeletal muscle membranes (IC50 = 15 nM), (b) KCl-stimulated calcium flux into cultured PC12 cells (IC50 = 81 nM), and (c) CaCl2-induced contractions of rabbit thoracic aortic strips (pA2 = 8.84). AHR-16303B had little or no effect on binding of radioligands to dopamine2 (DA2) alpha 1, alpha 2, H1, 5-HT1 alpha, beta 2, muscarinic M1, or sigma opioid receptors; had no effect on 5-HT3 receptor-mediated vagal bradycardia; and had only minor negative inotropic, chronotropic, and dromotropic effects on isolated guinea pig atria. In conscious SHR, 30 mg/kg p.o. AHR-16303B completely prevented the vasopressor responses to i.v. 5-HT, and decreased blood pressure (BP) by 24% 3 h after dosing.« less

NK cells contribute to persistent airway inflammation and AHR during the later stage of RSV infection in mice.

PubMed

Long, Xiaoru; Xie, Jun; Zhao, Keting; Li, Wei; Tang, Wei; Chen, Sisi; Zang, Na; Ren, Luo; Deng, Yu; Xie, Xiaohong; Wang, Lijia; Fu, Zhou; Liu, Enmei

2016-10-01

RSV can lead to persistent airway inflammation and AHR and is intimately associated with childhood recurrent wheezing and asthma, but the underlying mechanisms remain unclear. There are high numbers of NK cells in the lung, which not only play important roles in the acute stage of RSV infection, but also are pivotal in regulating the pathogenesis of asthma. Therefore, in this study, we assumed that NK cells might contribute to persistent airway disease during the later stage of RSV infection. Mice were killed at serial time points after RSV infection to collect samples. Leukocytes in bronchoalveolar lavage fluid (BALF) were counted, lung histopathology was examined, and airway hyperresponsiveness (AHR) was measured by whole-body plethysmography. Cytokines were detected by ELISA, and NK cells were determined by flow cytometry. Rabbit anti-mouse asialo-GM-1 antibodies and resveratrol were used to deplete or suppress NK cells. Inflammatory cells in BALF, lung tissue damage and AHR were persistent for 60 days post-RSV infection. Type 2 cytokines and NK cells were significantly increased during the later stage of infection. When NK cells were decreased by the antibodies or resveratrol, type 2 cytokines, the persistent airway inflammation and AHR were all markedly reduced. NK cells can contribute to the RSV-associated persistent airway inflammation and AHR at least partially by promoting type 2 cytokines. Therefore, therapeutic targeting of NK cells may provide a novel approach to alleviating the recurrent wheezing subsequent to RSV infection.

Hexachlorobenzene induces cell proliferation, and aryl hydrocarbon receptor expression (AhR) in rat liver preneoplastic foci, and in the human hepatoma cell line HepG2. AhR is a mediator of ERK1/2 signaling, and cell cycle regulation in HCB-treated HepG2 cells.

PubMed

de Tomaso Portaz, Ana Clara; Caimi, Giselle Romero; Sánchez, Marcela; Chiappini, Florencia; Randi, Andrea S; Kleiman de Pisarev, Diana L; Alvarez, Laura

2015-10-02

Hexachlorobenzene (HCB) is a widespread environmental pollutant, and a liver tumor promoter in rodents. Depending on the particular cell lines studied, exposure to these compounds may lead to cell proliferation, terminal differentiation, or apoptosis. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is involved in drug and xenobiotic metabolism. AhR can also modulate a variety of cellular and physiological processes that can affect cell proliferation and cell fate determination. The mechanisms by which AhR ligands, both exogenous and endogenous, affect these processes involve multiple interactions between AhR and other signaling pathways. In the present study, we examined the effect of HCB on cell proliferation and AhR expression, using an initiation-promotion hepatocarcinogenesis protocol in rat liver and in the human-derived hepatoma cell line, HepG2. Female Wistar rats were initiated with a single dose of 100 mg/kg of diethylnitrosamine (DEN) at the start of the experiment. Two weeks later, daily dosing of 100 mg/kg HCB was maintained for 10 weeks. Partial hepatectomy was performed 3 weeks after initiation. The number and area of glutathione S-transferase-P (GST-P)-positive foci, in the rat liver were used as biomarkers of liver precancerous lesions. Immunohistochemical staining showed an increase in proliferating cell nuclear antigen (PCNA)-positive cells, along with enhanced AhR protein expression in hepatocytes within GST-P-positive foci of (DEN HCB) group, when compared to DEN. In a similar manner, Western blot analysis demonstrated that HCB induced PCNA and AhR protein expression in HepG2 cells. Flow cytometry assay indicated that the cells were accumulated at S and G2/M phases of the cell cycle. HCB increased cyclin D1 protein levels and ERK1/2 phosphorylation in a dose-dependent manner. Treatment of cells with a selective MEK1 inhibitor, prevented HCB-stimulatory effect on PCNA and cyclinD1, indicating that these effects

Low levels of the AhR in chronic obstructive pulmonary disease (COPD)-derived lung cells increases COX-2 protein by altering mRNA stability

PubMed Central

Zago, Michela; Sheridan, Jared A.; Traboulsi, Hussein; Hecht, Emelia; Zhang, Yelu; Guerrina, Necola; Matthews, Jason; Nair, Parameswaran; Eidelman, David H.; Hamid, Qutayba

2017-01-01

Heightened inflammation, including expression of COX-2, is associated with chronic obstructive pulmonary disease (COPD) pathogenesis. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is reduced in COPD-derived lung fibroblasts. The AhR also suppresses COX-2 in response to cigarette smoke, the main risk factor for COPD, by destabilizing the Cox-2 transcript by mechanisms that may involve the regulation of microRNA (miRNA). Whether reduced AhR expression is responsible for heightened COX-2 in COPD is not known. Here, we investigated the expression of COX-2 as well as the expression of miR-146a, a miRNA known to regulate COX-2 levels, in primary lung fibroblasts derived from non-smokers (Normal) and smokers (At Risk) with and without COPD. To confirm the involvement of the AhR, AhR knock-down via siRNA in Normal lung fibroblasts and MLE-12 cells was employed as were A549-AhRko cells. Basal expression of COX-2 protein was higher in COPD lung fibroblasts compared to Normal or Smoker fibroblasts but there was no difference in Cox-2 mRNA. Knockdown of AhR in lung structural cells increased COX-2 protein by stabilizing the Cox-2 transcript. There was less induction of miR-146a in COPD-derived lung fibroblasts but this was not due to the AhR. Instead, we found that RelB, an NF-κB protein, was required for transcriptional induction of both Cox-2 and miR-146a. Therefore, we conclude that the AhR controls COX-2 protein via mRNA stability by a mechanism independent of miR-146a. Low levels of the AhR may therefore contribute to the heightened inflammation common in COPD patients. PMID:28749959

Low levels of the AhR in chronic obstructive pulmonary disease (COPD)-derived lung cells increases COX-2 protein by altering mRNA stability.

PubMed

Zago, Michela; Sheridan, Jared A; Traboulsi, Hussein; Hecht, Emelia; Zhang, Yelu; Guerrina, Necola; Matthews, Jason; Nair, Parameswaran; Eidelman, David H; Hamid, Qutayba; Baglole, Carolyn J

2017-01-01

Heightened inflammation, including expression of COX-2, is associated with chronic obstructive pulmonary disease (COPD) pathogenesis. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is reduced in COPD-derived lung fibroblasts. The AhR also suppresses COX-2 in response to cigarette smoke, the main risk factor for COPD, by destabilizing the Cox-2 transcript by mechanisms that may involve the regulation of microRNA (miRNA). Whether reduced AhR expression is responsible for heightened COX-2 in COPD is not known. Here, we investigated the expression of COX-2 as well as the expression of miR-146a, a miRNA known to regulate COX-2 levels, in primary lung fibroblasts derived from non-smokers (Normal) and smokers (At Risk) with and without COPD. To confirm the involvement of the AhR, AhR knock-down via siRNA in Normal lung fibroblasts and MLE-12 cells was employed as were A549-AhRko cells. Basal expression of COX-2 protein was higher in COPD lung fibroblasts compared to Normal or Smoker fibroblasts but there was no difference in Cox-2 mRNA. Knockdown of AhR in lung structural cells increased COX-2 protein by stabilizing the Cox-2 transcript. There was less induction of miR-146a in COPD-derived lung fibroblasts but this was not due to the AhR. Instead, we found that RelB, an NF-κB protein, was required for transcriptional induction of both Cox-2 and miR-146a. Therefore, we conclude that the AhR controls COX-2 protein via mRNA stability by a mechanism independent of miR-146a. Low levels of the AhR may therefore contribute to the heightened inflammation common in COPD patients.

Dose- and time-dependent expression of aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (ARNT) in PCB-, B[a]P-, and TBT-exposed intertidal copepod Tigriopus japonicus.

PubMed

Kim, Bo-Mi; Rhee, Jae-Sung; Hwang, Un-Ki; Seo, Jung Soo; Shin, Kyung-Hoon; Lee, Jae-Seong

2015-02-01

The aryl hydrocarbon receptor (AhR) and aryl hydrocarbon nuclear translocator (ARNT) genes from the copepod Tigriopus japonicus (Tj) were cloned to examine their potential functions in the invertebrate putative AhR-CYP signaling pathway. The amino acid sequences encoded by the Tj-AhR and Tj-ARNT genes showed high similarity to homologs of Daphnia and Drosophila, ranging from 68% and 70% similarity for the AhR genes to 56% for the ARNT genes. To determine whether Tj-AhR and Tj-ARNT are modulated by environmental pollutants, transcriptional expression of Tj-AhR and Tj-ARNT was analyzed in response to exposure to five concentrations of polychlorinated biphenyl (PCB 126) (control, 10, 50, 100, 500 μg L(-1)), benzo[a]pyrene (B[a]P) (control, 5, 10, 50, 100 μg L(-1)), and tributyltin (TBT) (control, 1, 5, 10, 20 μg L(-1)) 24h after exposure. A time-course experiment (0, 3, 6, 12, 24h) was performed to analyze mRNA expression patterns after exposure to PCB, B[a]P, and TBT. T. japonicus exhibited dose-dependent and time-dependent upregulation of Tj-AhR and Tj-ARNT in response to pollutant exposure, and the degree of expression was dependent on the pollutant, suggesting that pollutants such as PCB, B[a]P, and TBT modulate expression of Tj-AhR and Tj-ARNT genes in the putative AhR-CYP signaling pathway. Copyright © 2014 Elsevier Ltd. All rights reserved.

TCDD promoted EMT of hFPECs via AhR, which involved the activation of EGFR/ERK signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gao, Zhan; The Fifth Affiliated Hospital, Zhengzhou University, 450052; Bu, Yongjun

2016-05-01

One critical step of second palatal fusion is the newly formed medial epithelia seam (MES) disintegration, which involves apoptosis, epithelial to mesenchymal transition (EMT), and cell migration. Although the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces cleft palate at high rates, little is known about the effects of TCDD exposure on the fate of palatal epithelial cells. By using primary epithelial cells isolated from human fetal palatal shelves (hFPECs), we show that TCDD increased cell proliferation and EMT, as demonstrated by increased the epithelial markers (E-cadherin and cytokeratin14) and enhanced the mesenchymal markers (vimentin and fibronectin), but had no effect on cellmore » migration and apoptosis. TCDD exposure led to a dose-dependent increase in Slug protein expression. Coimmunoprecipitation revealed that TCDD promoted AhR to form a protein complex with Slug. ChIP assay confirmed that TCDD exposure recruited AhR to the xenobiotic responsive element of Slug promoter. Knockdown of AhR by siRNA remarkably weakened TCDD-induced binding of AhR to the XRE promoter of slug, thereby suppressed TCDD-induced vimentin. Further experiment showed that TCDD stimulated EGFR phosphorylation did not influence the TGFβ3/Smad signaling; whereas TCDD increased phosphorylation of ERK1/2 and p38 with no effect on activation of JNK. By using varieties of inhibitors, we confirmed that TCDD promoted proliferation and EMT of hFPECs via activation of EGFR/ERK pathway. These data make a novel contribution to the molecular mechanism of cleft palate by TCDD. - Highlights: • TCDD exposure promoted cell proliferation and EMT of hFPECs; • AhR signaling was activated and required for TCDD-induced EMT; • TCDD-mediated EMT of hFPECs involved the activation of EGFR/ERK signaling; • TCDD exposure had no effect on TGFβ3/Smad pathway.« less

Gene expression and inducibility of the aryl hydrocarbon receptor-dependent pathway in cultured bovine blood lymphocytes.

PubMed

Girolami, Flavia; Spalenza, Veronica; Carletti, Monica; Perona, Giovanni; Sacchi, Paola; Rasero, Roberto; Nebbia, Carlo

2011-10-10

The exposure to dioxin-like (DL) compounds, an important class of persistent environmental pollutants, results in the altered expression of target genes. This occurs through the binding to the aryl hydrocarbon receptor (AhR), the subsequent dimerization with the AhR nuclear translocator (ARNT), and the binding of the complex to DNA responsive elements. A number of genes are up-regulated, including, among others, the AhR repressor (AHRR) and several biotransformation enzymes, such as the members of CYP1 family and NAD(P)H-quinone oxidoreductase (NOQ1). The expression and the inducibility of the above genes were investigated in mitogen-stimulated cultured blood lymphocytes from cattle, which represent a notable source of DL-compound human exposure through dairy products and meat. As assessed by real-time PCR, all the examined genes except CYP1A2 and NQO1 were detected under basal conditions. Cell exposure to the DL-compounds PCB126 or PCB77 in the 10(-6)-10(-9)M concentration range resulted in a 2-4-fold induction of CYPIA1 and CYP1B1, which was antagonized by α-naphthoflavone or PCB153. This study demonstrates for the first time the presence and inducibility of the AhR pathway in easily accessible cells like bovine peripheral lymphocytes and prompts further investigations to verify whether similar changes could occur under in vivo conditions. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

A high-resolution structure of the DNA-binding domain of AhrC, the arginine repressor/activator protein from Bacillus subtilis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garnett, James A.; Baumberg, Simon; Stockley, Peter G.

2007-11-01

The structure of the winged helix–turn–helix DNA-binding domain of AhrC has been determined at 1.0 Å resolution. The largely hydrophobic β-wing shows high B factors and may mediate the dimer interface in operator complexes. In Bacillus subtilis the concentration of l-arginine is controlled by the transcriptional regulator AhrC, which interacts with 18 bp DNA operator sites called ARG boxes in the promoters of arginine biosynthetic and catabolic operons. AhrC is a 100 kDa homohexamer, with each subunit having two domains. The C-terminal domains form the core, mediating intersubunit interactions and binding of the co-repressor l-arginine, whilst the N-terminal domains containmore » a winged helix–turn–helix DNA-binding motif and are arranged around the periphery. The N-terminal domain of AhrC has been expressed, purified and characterized and it has been shown that the fragment still binds DNA operators as a recombinant monomer. The DNA-binding domain has also been crystallized and the crystal structure refined to 1.0 Å resolution is presented.« less

AHR-Enhancing γδ T Cells Develop in Normal Untreated Mice and Fail to Produce IL-4/13, Unlike TH2 Cells and NKT Cells1

PubMed Central

Jin, Niyun; Roark, Christina L.; Miyahara, Nobuaki; Taube, Christian; Aydintug, M. Kemal; Wands, JM; Huang, Yafei; Hahn, Youn-Soo; Gelfand, Erwin W.; O’Brien, Rebecca L.; Born, Willi K.

2008-01-01

Allergic airway hyperresponsiveness (AHR) in OVA-sensitized and challenged mice, mediated by allergen-specific Th2 cells and Th2-like iNKT cells, develops under the influence of enhancing and inhibitory γδ T cells. The AHR-enhancing cells belong to the Vγ1+ γδ T cell subset, cells that are capable of increasing IL-5 and IL-13 levels in the airways in a manner like Th2 cells. They also synergize with iNKT cells in mediating AHR. However, unlike Th2 cells, the AHR-enhancers arise in untreated mice, and we show here that they exhibit their functional bias already as thymocytes, at an HSAhi maturational stage. In further contrast to Th2 cells and also unlike iNKT cells, they could not be stimulated to produce IL-4 and IL-13, consistent with their synergistic dependence on iNKT cells in mediating AHR. Mice deficient in IFN-γ, TNFRp75 or IL-4 did not produce these AHR-enhancing γδ T cells, but in the absence of IFN-γ, their spontaneous development was restored by adoptive transfer of IFN-γ competent dendritic cells from untreated donors. Intra-peritoneal injection of OVA/alum restored development of the AHR-enhancers in all of the mutant strains, indicating that the enhancers still can be induced when they fail to develop spontaneously, and that they themselves need not express TNFRp75, IFN-γ or IL-4 in order to exert their function. We conclude that both the development and the cytokine potential of the AHR-enhancing γδ T cells differs critically from that of Th2 cells and NKT cells, despite similar influences of these cell populations on AHR. PMID:19201853

A luciferase reporter gene assay and aryl hydrocarbon receptor 1 genotype predict the LD{sub 50} of polychlorinated biphenyls in avian species

DOE Office of Scientific and Technical Information (OSTI.GOV)

Manning, Gillian E., E-mail: gmann017@uottawa.ca; Environment Canada, National Wildlife Research Centre, Ottawa, ON, Canada K1A 0H3; Farmahin, Reza, E-mail: mfarm070@uottawa.ca

2012-09-15

Birds differ in sensitivity to the embryotoxic effects of polychlorinated biphenyls (PCBs), which complicates environmental risk assessments for these chemicals. Recent research has shown that the identities of amino acid residues 324 and 380 in the avian aryl hydrocarbon receptor 1 (AHR1) ligand binding domain (LBD) are primarily responsible for differences in avian species sensitivity to selected dibenzo-p-dioxins and furans. A luciferase reporter gene (LRG) assay was developed in our laboratory to measure AHR1-mediated induction of a cytochrome P450 1A5 reporter gene in COS-7 cells transfected with different avian AHR1 constructs. In the present study, the LRG assay was usedmore » to measure the concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and PCBs 126, 77, 105 and 118 on luciferase activity in COS-7 cells transfected with AHR1 constructs representative of 86 avian species in order to predict their sensitivity to PCB-induced embryolethality and the relative potency of PCBs in these species. The results of the LRG assay indicate that the identity of amino acid residues 324 and 380 in the AHR1 LBD are the major determinants of avian species sensitivity to PCBs. The relative potency of PCBs did not differ greatly among AHR1 constructs. Luciferase activity was significantly correlated with embryolethality data obtained from the literature (R{sup 2} ≥ 0.87, p < 0.0001). Thus, the LRG assay in combination with the knowledge of a species' AHR1 LBD sequence can be used to predict PCB-induced embryolethality in potentially any avian species of interest without the use of lethal methods on a large number of individuals. -- Highlights: ► PCB embryolethality in birds can be predicted from a species' AHR1 genotype. ► The reporter gene assay is useful for predicting species sensitivity to PCBs. ► The relative potency of PCBs does not appear to differ between AHR1 genotypes. ► Contamination of PCB 105 and PCB 118 did not affect

75 FR 49550 - Fifth Meeting: RTCA Special Committee 219: Attitude and Heading Reference System (AHRS)

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-13

... 219: Attitude and Heading Reference System (AHRS) AGENCY: Federal Aviation Administration (FAA), Department of Transportation (DOT). ACTION: Notice of RTCA Special Committee 219: Attitude and Heading... 49551

Combined chemical and toxicological long-term monitoring for AhR agonists with SPMD-based virtual organisms in drinking water Danjiangkou Reservoir, China.

PubMed

Wang, Jingxian; Song, Guoqiang; Li, Aimin; Henkelmann, Bernhard; Pfister, Gerd; Tong, Anthony Z; Schramm, Karl-Werner

2014-08-01

SPMD-based virtual organisms (VOs) were employed for time-integrating, long-term sampling combined biological and chemical analyses for exposure assessment of hydrophobic organic pollutants (HOPs) in a drinking water reservoir, China. The SPMDs were deployed at four and five sites in the Danjiangkou (DJK) reservoir over two periods of 26 and 31 d to sequester the hydrophobic contaminants in water. The chosen bioassay response for the extracts of the SPMDs, the induction of 7-ethoxyresorufin-o-deethylase (EROD) was assayed using a rat hepatoma cell line (H4IIE). The known aryl hydrocarbon receptor (AhR) agonists PAHs and PCBs were analyzed by HRGC/HRMS instrument. The cause-effect relationship between the observed AhR activities and chemical concentrations of detected AhR agonists was examined. The results show that the extracts from the SPMD samples could induce AhR activity significantly, whereas the chemically derived 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalent (TEQcal) was not correlated with the bioassay-derived TCDD equivalent (TEQbio). The known AhR agonists could only account for 2-10% of the observed AhR responses among which the contribution of PCBs could almost be neglected. Unidentified AhR-active compounds represented a greater proportion of the TCDD equivalent (TCDD-EQ) in SPMD samples from DJK. Based on the first assessment, the VO followed by the combination of chemical and biological analyses emerges as a resource efficient water monitoring device in ecotoxicological assessment for toxicologically relevant compounds which are readily available for uptake by resident aquatic biota in drinking water resources. Copyright © 2014 Elsevier Ltd. All rights reserved.

Lipophilic components of diesel exhaust particles induce pro-inflammatory responses in human endothelial cells through AhR dependent pathway(s).

PubMed

Brinchmann, Bendik C; Skuland, Tonje; Rambøl, Mia H; Szoke, Krisztina; Brinchmann, Jan E; Gutleb, Arno C; Moschini, Elisa; Kubátová, Alena; Kukowski, Klara; Le Ferrec, Eric; Lagadic-Gossmann, Dominique; Schwarze, Per E; Låg, Marit; Refsnes, Magne; Øvrevik, Johan; Holme, Jørn A

2018-05-11

Exposure to traffic-derived particulate matter (PM), such as diesel exhaust particles (DEP), is a leading environmental cause of cardiovascular disease (CVD), and may contribute to endothelial dysfunction and development of atherosclerosis. It is still debated how DEP and other inhaled PM can contribute to CVD. However, organic chemicals (OC) adhered to the particle surface, are considered central to many of the biological effects. In the present study, we have explored the ability of OC from DEP to reach the endothelium and trigger pro-inflammatory reactions, a central step on the path to atherosclerosis. Exposure-relevant concentrations of DEP (0.12 μg/cm 2 ) applied on the epithelial side of an alveolar 3D tri-culture, rapidly induced pro-inflammatory and aryl hydrocarbon receptor (AhR)-regulated genes in the basolateral endothelial cells. These effects seem to be due to soluble lipophilic constituents rather than particle translocation. Extractable organic material of DEP (DEP-EOM) was next fractionated with increasing polarity, chemically characterized, and examined for direct effects on pro-inflammatory and AhR-regulated genes in human microvascular endothelial (HMEC-1) cells and primary human endothelial cells (PHEC) from four healthy donors. Exposure-relevant concentrations of lipophilic DEP-EOM (0.15 μg/cm 2 ) induced low to moderate increases in IL-1α, IL-1β, COX2 and MMP-1 gene expression, and the MMP-1 secretion was increased. By contrast, the more polar EOM had negligible effects, even at higher concentrations. Use of pharmacological inhibitors indicated that AhR and protease-activated receptor-2 (PAR-2) were central in regulation of EOM-induced gene expression. Some effects also seemed to be attributed to redox-responses, at least at the highest exposure concentrations tested. Although the most lipophilic EOM, that contained the majority of PAHs and aliphatics, had the clearest low-concentration effects, there was no straight-forward link

A rapid and reagent-free bioassay for the detection of dioxin-like compounds and other aryl hydrocarbon receptor (AhR) agonists using autobioluminescent yeast.

PubMed

Xu, Tingting; Young, Anna; Marr, Enolia; Sayler, Gary; Ripp, Steven; Close, Dan

2018-02-01

An autonomously bioluminescent Saccharomyces cerevisiae BLYAhS bioreporter was developed in this study for the simple and rapid detection of dioxin-like compounds (DLCs) and aryl hydrocarbon receptor (AhR) agonists. This recombinant yeast reporter was based on a synthetic bacterial luciferase reporter gene cassette (lux) that can produce the luciferase as well as the enzymes capable of self-synthesizing the requisite substrates for bioluminescent production from endogenous cellular metabolites. As a result, bioluminescent signal production is generated continuously and autonomously without cell lysis or exogenous reagent addition. By linking the expression of the autobioluminescent lux reporter cassette to AhR activation via the use of a dioxin-responsive promoter, the S. cerevisiae BLYAhS bioreporter emitted a bioluminescent signal in response to DLC exposure in a dose-responsive manner. The model dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), could be detected within 4 h with a half maximal effective concentration (EC 50 ) of ~ 8.1 nM and a lower detection limit of 500 pM. The autobioluminescent response of BLYAhS to other AhR agonists, including 2,3,7,8-tetrachlorodibenzofuran (TCDF), polychlorinated bisphenyl congener 126 (PCB-126) and 169 (PCB-169), 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD), 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), benzo[a]pyrene (BaP), and β-naphthoflavone (bNF), were also characterized in this study. The non-destructive and reagent-free nature of the BLYAhS reporter assay facilitated near-continuous, automated signal acquisition without additional hands-on effort and cost, providing a simple and cost-effective method for rapid DLC detection.

A luciferase reporter gene assay and aryl hydrocarbon receptor 1 genotype predict the LD50 of polychlorinated biphenyls in avian species.

PubMed

Manning, Gillian E; Farmahin, Reza; Crump, Doug; Jones, Stephanie P; Klein, Jeff; Konstantinov, Alex; Potter, Dave; Kennedy, Sean W

2012-09-15

Birds differ in sensitivity to the embryotoxic effects of polychlorinated biphenyls (PCBs), which complicates environmental risk assessments for these chemicals. Recent research has shown that the identities of amino acid residues 324 and 380 in the avian aryl hydrocarbon receptor 1 (AHR1) ligand binding domain (LBD) are primarily responsible for differences in avian species sensitivity to selected dibenzo-p-dioxins and furans. A luciferase reporter gene (LRG) assay was developed in our laboratory to measure AHR1-mediated induction of a cytochrome P450 1A5 reporter gene in COS-7 cells transfected with different avian AHR1 constructs. In the present study, the LRG assay was used to measure the concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and PCBs 126, 77, 105 and 118 on luciferase activity in COS-7 cells transfected with AHR1 constructs representative of 86 avian species in order to predict their sensitivity to PCB-induced embryolethality and the relative potency of PCBs in these species. The results of the LRG assay indicate that the identity of amino acid residues 324 and 380 in the AHR1 LBD are the major determinants of avian species sensitivity to PCBs. The relative potency of PCBs did not differ greatly among AHR1 constructs. Luciferase activity was significantly correlated with embryolethality data obtained from the literature (R(2)≥0.87, p<0.0001). Thus, the LRG assay in combination with the knowledge of a species' AHR1 LBD sequence can be used to predict PCB-induced embryolethality in potentially any avian species of interest without the use of lethal methods on a large number of individuals. Copyright © 2012 Elsevier Inc. All rights reserved.

In Vitro Antitumor Effects of AHR Ligands Aminoflavone (AFP 464) and Benzothiazole (5F 203) in Human Renal Carcinoma Cells.

PubMed

Luzzani, Gabriela A; Callero, Mariana A; Kuruppu, Anchala I; Trapani, Valentina; Flumian, Carolina; Todaro, Laura; Bradshaw, Tracey D; Loaiza Perez, Andrea I

2017-12-01

We investigated activity and mechanism of action of two AhR ligand antitumor agents, AFP 464 and 5F 203 on human renal cancer cells, specifically examining their effects on cell cycle progression, apoptosis, and migration. TK-10, SN12C, Caki-1, and ACHN human renal cancer cell lines were treated with AFP 464 and 5F 203. We evaluated cytotoxicity by MTS assays, cell cycle arrest, and apoptosis by flow cytometry and corroborated a mechanism of action involving AhR signal transduction activation. Changes in migration properties by wound healing assays were investigated: 5F 203-sensitive cells show decreased migration after treatment, therefore, we measured c-Met phosphorylation by Western blot in these cells. A 5F 203 induced a decrease in cell viability which was more marked than AFP 464. This cytotoxicity was reduced after treatment with the AhR inhibitor α-NF for both compounds indicating AhR signaling activation plays a role in the mechanism of action. A 5F 203 is sequestered by TK-10 cells and induces CYP1A1 expression; 5F 203 potently inhibited migration of TK-10, Caki-1, and SN12C cells, and inhibited c-Met receptor phosphorylation in TK-10 cells. AhR ligand antitumor agents AFP 464 and 5F 203 represent potential new candidates for the treatment of renal cancer. A 5F 203 only inhibited migration of sensitive cells and c-Met receptor phosphorylation in TK-10 cells. c-Met receptor signal transduction is important in migration and metastasis. Therefore, we consider that 5F 203 offers potential for the treatment of metastatic renal carcinoma. J. Cell. Biochem. 118: 4526-4535, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Baicalein induces G1 arrest in oral cancer cells by enhancing the degradation of cyclin D1 and activating AhR to decrease Rb phosphorylation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Ya-Hsin, E-mail: yhcheng@mail.cmu.edu.tw; Li, Lih-Ann; Lin, Pinpin

Baicalein is a flavonoid, known to have anti-inflammatory and anti-cancer effects. As an aryl hydrocarbon receptor (AhR) ligand, baicalein at high concentrations blocks AhR-mediated dioxin toxicity. Because AhR had been reported to play a role in regulating the cell cycle, we suspected that the anti-cancer effect of baicalein is associated with AhR. This study investigated the molecular mechanism involved in the anti-cancer effect of baicalein in oral cancer cells HSC-3, including whether such effect would be AhR-mediated. Results revealed that baicalein inhibited cell proliferation and increased AhR activity in a dose-dependent manner. Cell cycle was arrested at the G1 phasemore » and the expression of CDK4, cyclin D1, and phosphorylated retinoblastoma (pRb) was decreased. When the AhR was suppressed by siRNA, the reduction of pRb was partially reversed, accompanied by a decrease of cell population at G1 phase and an increase at S phase, while the reduction of cyclin D1 and CDK4 did not change. This finding suggests that the baicalein activation of AhR is indeed associated with the reduction of pRb, but is independent of the reduction of cyclin D1 and CDK4. When cells were pre-treated with LiCl, the inhibitor of GSK-3β, the decrease of cyclin D1 was blocked and the reduction of pRb was recovered. The data indicates that in HSC-3 the reduction of pRb is both mediated by baicalein through activation of AhR and facilitation of cyclin D1 degradation, which causes cell cycle arrest at the G1 phase, and results in the inhibition of cell proliferation. -- Highlights: ► Baicalein causes the G1 phase arrest by decreasing Rb phosphorylation. ► Baicalein modulates AhR-mediated cell proliferation. ► Both AhR activation and cyclin D1 degradation results in hypophosphorylation of Rb. ► Baicalein facilitates cyclin D1 degradation by signalling the GSK-3β pathway.« less

RELATIONSHIPS BETWEEN RESIDUES OF AHR AGONISTS IN FISH AND CONCENTRATIONS IN WATER AND SEDIMENTS

EPA Science Inventory

Relationships between Residues of AhR Agonists in Fish and Concentrations in Water and Sediment. Cook, PM*, Burkhard, LP, Mount, DR, US-EPA, NHEERL, MED, Duluth, MN. The bioaccumulation visualization approach of Burkhard et al. (2002) can be effectively used to describe the bioa...

An endogenous aryl hydrocarbon receptor (AhR) ligand, ITE induces regulatory T cells (Tregs) and ameliorates experimental colitis.

PubMed

Abron, Jessicca D; Singh, Narendra P; Mishra, Manoj K; Price, Robert L; Nagarkatti, Mitzi; Nagarkatti, Prakash S; Singh, Udai P

2018-04-19

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that affects millions of people with high morbidity and health-care cost. The precise etiology of IBD is unknown, but clear evidence suggests that intestinal inflammation is caused by an excessive immune response to mucosal antigens. Recent studies have shown that activation of the aryl hydrocarbon receptor (AhR) induces regulatory T cells (Tregs) and suppresses autoimmune diseases. In the current study, we investigated if nontoxic ligand of AhR, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), can attenuate dextran sodium sulphate (DSS)-induced colitis. Our studies demonstrated that in mice that received ITE treatment, in-vivo colitis pathogenesis, including a decrease in body weight, was significantly reversed along with the systemic and intestinal inflammatory cytokines. ITE increased the expression of Tregs in spleen, mesenteric lymph nodes (MLNs) and colon lamina propria lymphocytes (cLPL) of mice with colitis when compared to controls. This induction of Tregs was reversed by AhR antagonist treatment in-vitro. ITE treatment also increased dendritic cells (DCs; CD11c+) and decreased F4/80+ (macrophage) from the spleen, MLNs and cLPL in mice with colitis. ITE also reversed the systemic and intestinal frequency of CD4+T cells during colitis and suppressed inflammatory cytokines including IFN-γ, TNF-α, IL-17, IL-6 and IL-1 as well as induced IL-10 levels. These findings suggest that ITE attenuates colitis through induction of Tregs and reduction in inflammatory CD4+ T cells and cytokines. Thus, our work demonstrates that the nontoxic endogenous AhR ligand ITE, may serve as a therapeutic modality to treat IBD.

Li-ion cells for terrestrial robots

NASA Technical Reports Server (NTRS)

Chin, Keith B.; Smart, M. C.; Narayanan, S. R.; Ratnakumar, B. V.; Whitcanack, L. D.; Davies, E. D.; Surampudi, S.; Raman, N. S.

2003-01-01

SAFT prismatic wound 5 Ahr MP series cells were evaluated for potential application in a lithium ion battery designed for Tactical Mobile Robots (TMR). In order to satisfy battery design requirements, a 10 Ahr battery containing two parallel 8-cell strings was proposed. The proposed battery has a weight and volume of approximately 3.2kg and 1.6 liters, respectively. Cell qualification procedures include initial characterization, followed by charge/discharge cycling at 100% DOD with intermittent EIS measurements at various state of charge. Certain cells were also subjected to extreme operational temperatures for worst-case analysis. Excellent specific energy (>130 Whr/kg) was obtained with initial characterization cycles. Even at abusive thermal conditions, the cell capacity fade was less than Ahr after 300 cycles. Rate characterization showed good cell discharge behavior with minimal decrease in capacity. At various state of charge, impedance measurements suggest that the cathode play a more significant role in capacity. At various state of charge impedance measurements suggest that the cathode play a more significant role in capacity fade than the anode.

EXPRESSION OF AHR AND ARNT MRNA IN CULTURED HUMAN ENDOMETRIAL EXPLANTS EXPOSED TO TCDD

EPA Science Inventory

Expression of AhR and ARNT mRNA in cultured human endometrial explants exposed to TCDD.

Pitt JA, Feng L, Abbott BD, Schmid J, Batt RE, Costich TG, Koury ST, Bofinger DP.

Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599, USA.

Endom...

Identification of aryl hydrocarbon receptor binding targets in mouse hepatic tissue treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lo, Raymond; Celius, Trine; Forgacs, Agnes L.

2011-11-15

Genome-wide, promoter-focused ChIP-chip analysis of hepatic aryl hydrocarbon receptor (AHR) binding sites was conducted in 8-week old female C57BL/6 treated with 30 {mu}g/kg/body weight 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 2 h and 24 h. These studies identified 1642 and 508 AHR-bound regions at 2 h and 24 h, respectively. A total of 430 AHR-bound regions were common between the two time points, corresponding to 403 unique genes. Comparison with previous AHR ChIP-chip studies in mouse hepatoma cells revealed that only 62 of the putative target genes overlapped with the 2 h AHR-bound regions in vivo. Transcription factor binding site analysis revealed anmore » over-representation of aryl hydrocarbon response elements (AHREs) in AHR-bound regions with 53% (2 h) and 68% (24 h) of them containing at least one AHRE. In addition to AHREs, E2f-Myc activator motifs previously implicated in AHR function, as well as a number of other motifs, including Sp1, nuclear receptor subfamily 2 factor, and early growth response factor motifs were also identified. Expression microarray studies identified 133 unique genes differentially regulated after 4 h treatment with TCDD. Of which, 39 were identified as AHR-bound genes at 2 h. Ingenuity Pathway Analysis on the 39 AHR-bound TCDD responsive genes identified potential perturbation in biological processes such as lipid metabolism, drug metabolism, and endocrine system development as a result of TCDD-mediated AHR activation. Our findings identify direct AHR target genes in vivo, highlight in vitro and in vivo differences in AHR signaling and show that AHR recruitment does not necessarily result in changes in target gene expression. -- Highlights: Black-Right-Pointing-Pointer ChIP-chip analysis of hepatic AHR binding after 2 h and 24 h of TCDD. Black-Right-Pointing-Pointer We identified 1642 and 508 AHR-bound regions at 2 h and 24 h. Black-Right-Pointing-Pointer 430 regions were common to both time points and highly enriched

AhR activation increases IL-2 production by alloreactive CD4+ T cells initiating the differentiation of mucosal-homing Tim3+ Lag3+ Tr1 cells.

PubMed

Ehrlich, Allison K; Pennington, Jamie M; Tilton, Susan; Wang, Xisheng; Marshall, Nikki B; Rohlman, Diana; Funatake, Castle; Punj, Sumit; O'Donnell, Edmond; Yu, Zhen; Kolluri, Siva K; Kerkvliet, Nancy I

2017-11-01

Activation of the aryl hydrocarbon receptor (AhR) by immunosuppressive ligands promotes the development of regulatory T (Treg) cells. Although AhR-induced Foxp3 + Treg cells have been well studied, much less is known about the development and fate of AhR-induced Type 1 Treg (AhR-Tr1) cells. In the current study, we identified the unique transcriptional and functional changes in murine CD4 + T cells that accompany the differentiation of AhR-Tr1 cells during the CD4 + T-cell-dependent phase of an allospecific cytotoxic T lymphocyte (allo-CTL) response. AhR activation increased the expression of genes involved in T-cell activation, immune regulation and chemotaxis, as well as a global downregulation of genes involved in cell cycling.  Increased IL-2 production was responsible for the early AhR-Tr1 activation phenotype previously characterized as CD25 + CTLA4 + GITR + on day 2. The AhR-Tr1 phenotype was further defined by the coexpression of the immunoregulatory receptors Lag3 and Tim3 and non-overlapping expression of CCR4 and CCR9. Consistent with the increased expression of CCR9, real-time imaging showed enhanced migration of AhR-Tr1 cells to the lamina propria of the small intestine and colon. The discovery of mucosal imprinting of AhR-Tr1 cells provides an additional mechanism by which therapeutic AhR ligands can control immunopathology. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Deciphering Dimerization Modes of PAS Domains: Computational and Experimental Analyses of the AhR:ARNT Complex Reveal New Insights Into the Mechanisms of AhR Transformation

PubMed Central

Corrada, Dario; Soshilov, Anatoly A.; Denison, Michael S.

2016-01-01

The Aryl hydrocarbon Receptor (AhR) is a transcription factor that mediates the biochemical response to xenobiotics and the toxic effects of a number of environmental contaminants, including dioxins. Recently, endogenous regulatory roles for the AhR in normal physiology and development have also been reported, thus extending the interest in understanding its molecular mechanisms of activation. Since dimerization with the AhR Nuclear Translocator (ARNT) protein, occurring through the Helix-Loop-Helix (HLH) and PER-ARNT-SIM (PAS) domains, is needed to convert the AhR into its transcriptionally active form, deciphering the AhR:ARNT dimerization mode would provide insights into the mechanisms of AhR transformation. Here we present homology models of the murine AhR:ARNT PAS domain dimer developed using recently available X-ray structures of other bHLH-PAS protein dimers. Due to the different reciprocal orientation and interaction surfaces in the different template dimers, two alternative models were developed for both the PAS-A and PAS-B dimers and they were characterized by combining a number of computational evaluations. Both well-established hot spot prediction methods and new approaches to analyze individual residue and residue-pairwise contributions to the MM-GBSA binding free energies were adopted to predict residues critical for dimer stabilization. On this basis, a mutagenesis strategy for both the murine AhR and ARNT proteins was designed and ligand-dependent DNA binding ability of the AhR:ARNT heterodimer mutants was evaluated. While functional analysis disfavored the HIF2α:ARNT heterodimer-based PAS-B model, most mutants derived from the CLOCK:BMAL1-based AhR:ARNT dimer models of both the PAS-A and the PAS-B dramatically decreased the levels of DNA binding, suggesting this latter model as the most suitable for describing AhR:ARNT dimerization. These novel results open new research directions focused at elucidating basic molecular mechanisms underlying the

Deciphering Dimerization Modes of PAS Domains: Computational and Experimental Analyses of the AhR:ARNT Complex Reveal New Insights Into the Mechanisms of AhR Transformation.

PubMed

Corrada, Dario; Soshilov, Anatoly A; Denison, Michael S; Bonati, Laura

2016-06-01

The Aryl hydrocarbon Receptor (AhR) is a transcription factor that mediates the biochemical response to xenobiotics and the toxic effects of a number of environmental contaminants, including dioxins. Recently, endogenous regulatory roles for the AhR in normal physiology and development have also been reported, thus extending the interest in understanding its molecular mechanisms of activation. Since dimerization with the AhR Nuclear Translocator (ARNT) protein, occurring through the Helix-Loop-Helix (HLH) and PER-ARNT-SIM (PAS) domains, is needed to convert the AhR into its transcriptionally active form, deciphering the AhR:ARNT dimerization mode would provide insights into the mechanisms of AhR transformation. Here we present homology models of the murine AhR:ARNT PAS domain dimer developed using recently available X-ray structures of other bHLH-PAS protein dimers. Due to the different reciprocal orientation and interaction surfaces in the different template dimers, two alternative models were developed for both the PAS-A and PAS-B dimers and they were characterized by combining a number of computational evaluations. Both well-established hot spot prediction methods and new approaches to analyze individual residue and residue-pairwise contributions to the MM-GBSA binding free energies were adopted to predict residues critical for dimer stabilization. On this basis, a mutagenesis strategy for both the murine AhR and ARNT proteins was designed and ligand-dependent DNA binding ability of the AhR:ARNT heterodimer mutants was evaluated. While functional analysis disfavored the HIF2α:ARNT heterodimer-based PAS-B model, most mutants derived from the CLOCK:BMAL1-based AhR:ARNT dimer models of both the PAS-A and the PAS-B dramatically decreased the levels of DNA binding, suggesting this latter model as the most suitable for describing AhR:ARNT dimerization. These novel results open new research directions focused at elucidating basic molecular mechanisms underlying the

Accurate Orientation Estimation Using AHRS under Conditions of Magnetic Distortion

PubMed Central

Yadav, Nagesh; Bleakley, Chris

2014-01-01

Low cost, compact attitude heading reference systems (AHRS) are now being used to track human body movements in indoor environments by estimation of the 3D orientation of body segments. In many of these systems, heading estimation is achieved by monitoring the strength of the Earth's magnetic field. However, the Earth's magnetic field can be locally distorted due to the proximity of ferrous and/or magnetic objects. Herein, we propose a novel method for accurate 3D orientation estimation using an AHRS, comprised of an accelerometer, gyroscope and magnetometer, under conditions of magnetic field distortion. The system performs online detection and compensation for magnetic disturbances, due to, for example, the presence of ferrous objects. The magnetic distortions are detected by exploiting variations in magnetic dip angle, relative to the gravity vector, and in magnetic strength. We investigate and show the advantages of using both magnetic strength and magnetic dip angle for detecting the presence of magnetic distortions. The correction method is based on a particle filter, which performs the correction using an adaptive cost function and by adapting the variance during particle resampling, so as to place more emphasis on the results of dead reckoning of the gyroscope measurements and less on the magnetometer readings. The proposed method was tested in an indoor environment in the presence of various magnetic distortions and under various accelerations (up to 3 g). In the experiments, the proposed algorithm achieves <2° static peak-to-peak error and <5° dynamic peak-to-peak error, significantly outperforming previous methods. PMID:25347584

Perturbation effect of reduced graphene oxide quantum dots (rGOQDs) on aryl hydrocarbon receptor (AhR) pathway in zebrafish.

PubMed

Zhang, Jing-Hui; Sun, Tai; Niu, Aping; Tang, Yu-Mei; Deng, Shun; Luo, Wei; Xu, Qun; Wei, Dapeng; Pei, De-Sheng

2017-07-01

Graphene quantum dots (GQDs) has been widely used in enormous fields, however, the inherent molecular mechanism of GQDs for potential risks in biological system is still elusive to date. In this study, the outstanding reduced graphene quantum dots (rGOQDs) with the QY as high as 24.62% were successfully synthesized by the improved Hummers method and DMF hydrothermal treatment approach. The rGOQDs were N-doped photoluminescent nanomaterials with functional groups on the surface. The fluorescent bio-imaging was performed by exposing zebrafish in different concentrations of the as-prepared rGOQDs, and the distribution of rGOQDs was successfully observed. Moreover, the developmental toxicity and genotoxicity were evaluated to further investigate the potential hazard of rGOQDs. The result indicated that rGOQDs were responsible for the dose-dependent abnormalities on the development of zebrafish. Since the real-time polymerase chain reaction (RT-PCR) results showed that the expression of cyp1a was the highest expression in the selected genes and significantly up-regulated 8.49 fold in zebrafish, the perturbation of rGOQDs on aryl hydrocarbon receptor (AhR) pathway was investigated by using the Tg(cyp1a:gfp) zebrafish for the first time. The results demonstrated that rGOQDs significantly increased the green fluorescent protein (GFP) expression promoted by cyp1a in a dose-dependent manner, which was also further confirmed by the western blotting. This study offered an opportunity to reveal the potential hazards of in vivo bio-probes, which provided a valuable reference for investigating the graphene-based materials on the disturbance of AhR pathway in biological organisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dietary Polyphenols Increase Paraoxonase 1 Gene Expression by an Aryl Hydrocarbon Receptor-Dependent Mechanism

PubMed Central

Gouédard, Cédric; Barouki, Robert; Morel, Yannick

2004-01-01

Human paraoxonase 1 (PON-1) is a serum high-density lipoprotein-associated enzyme mainly secreted by the liver. It has endogenous and exogenous substrates and displays protective properties with respect to cardiovascular disease and organophosphate intoxication. In the HuH7 human hepatoma cell line, PON-1 activity and mRNA levels were increased by dietary polyphenolic compounds such as quercetin but also by toxic ligands of the aryl hydrocarbon receptor (AhR) such as 3-methylcholanthrene (3-MC). However, the 2,3,7,8-tetrachlorobenzo(p)dioxin (TCDD) was a poor inducer. Transient and stable transfection assays indicated that these compounds increased the PON-1 gene promoter activity in an AhR-dependent manner, since their effect was inhibited by 7-keto-cholesterol and AhR-directed short interfering RNA. Deletions and mutations studies showed that a xenobiotic responsive element (XRE)-like sequence within the PON-1 promoter mediated the effect of 3-MC and quercetin. In contrast with consensus XREs from the cytochrome P450 1A1 gene, the PON-1 XRE-like element mediated preferentially the effect of quercetin compared to the results seen with TCDD. Furthermore, AhR binding to this element was preferentially activated by quercetin. These observations provide a molecular mechanism for the regulation of the cardioprotective enzyme PON-1 by polyphenols. They suggest also that AhR ligands may differentially regulate gene expression depending on the DNA target sequence. PMID:15169886

Gene expression profiling of the Notch-AhR-IL22 axis at homeostasis and in response to tissue injury.

PubMed

Weidenbusch, Marc; Rodler, Severin; Song, Shangqing; Romoli, Simone; Marschner, Julian A; Kraft, Franziska; Holderied, Alexander; Kumar, Santosh; Mulay, Shrikant R; Honarpisheh, Mohsen; Kumar Devarapu, Satish; Lech, Maciej; Anders, Hans-Joachim

2017-12-22

Notch and interleukin-22 (IL-22) signaling are known to regulate tissue homeostasis and respond to injury in humans and mice, and the induction of endogenous aryl hydrocarbon receptor (Ahr) ligands through Notch links the two pathways in a hierarchical fashion. However in adults, the species-, organ- and injury-specific gene expression of the Notch-AhR-IL22 axis components is unknown. We therefore performed gene expression profiling of DLL1, DLL3, DLL4, DLK1, DLK2, JAG1, JAG2, Notch1, Notch2, Notch3, Notch4, ADAM17/TNF-α ADAM metalloprotease converting enzyme (TACE), PSEN1, basigin (BSG)/CD147, RBP-J, HES1, HES5, HEY1, HEYL, AHR, ARNT, ARNT2, CYP1A1, CYP24A1, IL-22, IL22RA1, IL22RA2, IL10RB, and STAT3 under homeostatic conditions in ten mature murine and human organs. Additionally, the expression of these genes was assessed in murine models of acute sterile inflammation and progressive fibrosis. We show that there are organ-specific gene expression profiles of the Notch-AhR-IL22 axis in humans and mice. Although there is an overall interspecies congruency, specific differences between human and murine expression signatures do exist. In murine tissues with AHR/ARNT expression CYP1A1 and IL-22 were correlated with HES5 and HEYL expression, while in human tissues no such correlation was found. Notch and AhR signaling are involved in renal inflammation and fibrosis with specific gene expression changes in each model. Despite the presence of all Notch pathway molecules in the kidney and a model-specific induction of Notch ligands, IL-22 was only up-regulated in acute inflammation, but rapidly down-regulated during regeneration. This implies that for targeting injury responses, e.g. via IL-22, species-specific differences, injury type and time points have to be considered. © 2017 The Author(s).

The tertiary structures of porcine AhR and ARNT proteins and molecular interactions within the TCDD/AhR/ARNT complex.

PubMed

Orlowska, Karina; Molcan, Tomasz; Swigonska, Sylwia; Sadowska, Agnieszka; Jablonska, Monika; Nynca, Anna; Jastrzebski, Jan P; Ciereszko, Renata E

2016-06-01

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by structurally diverse synthetic and natural chemicals, including toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In the present study, homology models of the porcine AhR-ligand binding domain (LBD) and the porcine aryl hydrocarbon receptor nuclear translocator-ligand binding domain (ARNT-LBD) were created on the basis of structures of closely related respective proteins i.e., human Hif-2α and ARNT. Molecular docking of TCDD to the porcine AhR-LBD model revealed high binding affinity (-8.8kcal/mol) between TCDD and the receptor. Moreover, formation of the TCDD/AhR-LBD complex was confirmed experimentally with the use of electrophoretic mobility shift assay (EMSA). It was found that TCDD (10nM, 2h of incubation) not only bound to the AhR in the porcine granulosa cells but also activated the receptor. The current study provides a framework for examining the key events involved in the ligand-dependent activation of the AhR. Copyright © 2016 Elsevier Inc. All rights reserved.

Protective effects of levamisole, acetylsalicylic acid, and α-tocopherol against dioxin toxicity measured as the expression of AhR and COX-2 in a chicken embryo model.

PubMed

Gostomska-Pampuch, Kinga; Ostrowska, Alicja; Kuropka, Piotr; Dobrzyński, Maciej; Ziółkowski, Piotr; Kowalczyk, Artur; Łukaszewicz, Ewa; Gamian, Andrzej; Całkosiński, Ireneusz

2017-04-01

Polychlorinated dibenzo-p-dioxins and dibenzofurans (dioxins) are classed as persistent organic pollutants and have adverse effects on multiple functions within the body. Dioxins are known carcinogens, immunotoxins, and teratogens. Dioxins are transformed in vivo, and interactions between the products and the aryl hydrocarbon receptor (AhR) lead to the formation of proinflammatory and toxic metabolites. The aim of this study was to determine whether α-tocopherol (vitamin E), acetylsalicylic acid (ASA), and levamisole can decrease the amount of damage caused by dioxins. Fertile Hubbard Flex commercial line chicken eggs were injected with solutions containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or containing TCDD and the test compounds. The chicken embryos and organs were analyzed after 7 and 13 days. The levels at which AhR and cyclooxygenase-2 (COX-2) proteins (which are induced during inflammation) were expressed were evaluated by performing immunohistochemical analyses on embryos treated with TCDD alone or with TCDD and the test compounds. TCDD caused developmental disorders and increased AhR and COX-2 expression in the chicken embryo tissues. Vitamin E, levamisole, ASA, and ASA plus vitamin E inhibited AhR and COX-2 expression in embryos after 7 days and decreased AhR and COX-2 expression in embryos after 13 days. ASA, levamisole, and ASA plus vitamin E weakened the immune response and prevented multiple organ changes. Vitamin E was not fully protective against developmental changes in the embryos.

Essential oils of culinary herbs and spices display agonist and antagonist activities at human aryl hydrocarbon receptor AhR.

PubMed

Bartoňková, Iveta; Dvořák, Zdeněk

2018-01-01

Essential oils (EOs) of culinary herbs and spices are used to flavor, color and preserve foods and drinks. Dietary intake of EOs is significant, deserving an attention of toxicologists. We examined the effects of 31 EOs of culinary herbs and spices on the transcriptional activity of human aryl hydrocarbon receptor (AhR), which is a pivotal xenobiotic sensor, having also multiple roles in human physiology. Tested EOs were sorted out into AhR-inactive ones (14 EOs) and AhR-active ones, including full agonists (cumin, jasmine, vanilla, bay leaf), partial agonists (cloves, dill, thyme, nutmeg, oregano) and antagonists (tarragon, caraway, turmeric, lovage, fennel, spearmint, star anise, anise). Major constituents (>10%) of AhR-active EOs were studied in more detail. We identified AhR partial agonists (carvacrol, ligustilide, eugenol, eugenyl acetate, thymol, ar-turmerone) and antagonists (trans-anethole, butylidine phtalide, R/S-carvones, p-cymene), which account for AhR-mediated activities of EOs of fennel, anise, star anise, caraway, spearmint, tarragon, cloves, dill, turmeric, lovage, thyme and oregano. We also show that AhR-mediated effects of some individual constituents of EOs differ from those manifested in mixtures. In conclusion, EOs of culinary herbs and spices are agonists and antagonists of human AhR, implying a potential for food-drug interactions and interference with endocrine pathways. Copyright © 2017 Elsevier Ltd. All rights reserved.

Changes in the expression of genes involved in the ovarian function of rats caused by daily exposure to 3-methylcholanthrene and their prevention by α-naphthoflavone.

PubMed

Rhon-Calderón, Eric Alejandro; Toro, Carlos Alejandro; Lomniczi, Alejandro; Galarza, Rocío Alejandra; Faletti, Alicia Graciela

2018-02-01

Daily exposure to low doses of 3-methylcholanthrene (3MC) during the pubertal period in rats disrupts both follicular growth and ovulation. Thus, to provide new insights into the toxicity mechanism of 3MC in the ovary, here we investigated the effect of daily exposure to 3MC on selected ovarian genes, the role of the aryl hydrocarbon receptor (AhR) and the level of epigenetic remodeling of histone post-transcriptional modifications. Immature rats were daily injected with 3MC (0.1 or 1 mg/kg) and mRNA expression of genes involved in different ovarian processes were evaluated. Of the 29 genes studied, 18 were up-regulated, five were down-regulated and six were not altered. To assess whether AhR was involved in these changes, we used the chromatin immunoprecipitation assay. 3MC increased AhR binding to promoter regions of genes involved in Notch signaling (Hes1, Jag1), activation of primordial follicles (Cdk2), cell adhesion (Icam1), stress and tumor progression (Dnajb6), apoptosis (Bax, Caspase-9) and expression of growth and transcription factors (Igf2, Sp1). Studying the trimethylation and acetylation of histone 3 (H3K4me3 and H3K9Ac, respectively) of these genes, we found that 3MC increased H3K4me3 in Cyp1a1, Jag1, Dnajb6, Igf2, Notch2, Adamts1, Bax and Caspase-9, and H3K9Ac in Cyp1a1, Jag1, Cdk2, Dnajb6, Igf2, Icam1, and Sp1. Co-treatment with α-naphthoflavone (αNF), a specific antagonist of AhR, prevented almost every 3MC-induced changes. Despite the low dose used in these experiments, daily exposure to 3MC induced changes in both gene expression and epigenomic remodeling, which may lead to premature ovarian failure.

Lightweight Battery Charge Regulator Used to Track Solar Array Peak Power

NASA Technical Reports Server (NTRS)

Soeder, James F.; Button, Robert M.

1999-01-01

A battery charge regulator based on the series-connected boost regulator (SCBR) technology has been developed for high-voltage spacecraft applications. The SCBR regulates the solar array power during insolation to prevent battery overcharge or undercharge conditions. It can also be used to provide regulated battery output voltage to spacecraft loads if necessary. This technology uses industry-standard dc-dc converters and a unique interconnection to provide size, weight, efficiency, fault tolerance, and modularity benefits over existing systems. The high-voltage SCBR shown in the photograph has demonstrated power densities of over 1000 watts per kilogram (W/kg). Using four 150-W dc-dc converter modules, it can process 2500 W of power at 120 Vdc with a minimum input voltage of 90 Vdc. Efficiency of the SCBR was 94 to 98 percent over the entire operational range. Internally, the unit is made of two separate SCBR s, each with its own analog control circuitry, to demonstrate the modularity of the technology. The analog controllers regulate the output current and incorporate the output voltage limit with active current sharing between the two units. They also include voltage and current telemetry, on/off control, and baseplate temperature sensors. For peak power tracking, the SCBR was connected to a LabView-based data acquisition system for telemetry and control. A digital control algorithm for tracking the peak power point of a solar array was developed using the principle of matching the source impedance with the load impedance for maximum energy transfer. The algorithm was successfully demonstrated in a simulated spacecraft electrical system at the Boeing PhantomWorks High Voltage Test Facility in Seattle, Washington. The system consists of a 42-string, high-voltage solar array simulator, a 77-cell, 80-ampere-hour (A-hr) nickel-hydrogen battery, and a constant power-load module. The SCBR and the LabView control algorithm successfully tracked the solar array peak

Characterization of AhR agonists reveals antagonistic activity in European herring gull (Larus argentatus) eggs.

PubMed

Muusse, Martine; Christensen, Guttorm; Gomes, Tânia; Kočan, Anton; Langford, Katherine; Tollefsen, Knut Erik; Vaňková, Lenka; Thomas, Kevin V

2015-05-01

European herring gull (Larus argentatus) eggs from two Norwegian islands, Musvær in the south east and Reiaren in Northern Norway, were screened for dioxins, furans, and dioxin-like and selected non-dioxin-like polychlorinated biphenyls (PCBs), and subjected to non-target analysis to try to identify the aryl hydrocarbon receptor (AhR) agonists, responsible for elevated levels measured using the dioxin responsive chemically activated luciferase expression (DR-CALUX) assay. Eggs from Musvær contained chemically calculated toxic equivalent (WHO TEQ) levels of between 109 and 483 pg TEQ/g lw, and between 82 and 337 pg TEQ/g lw was determined in eggs from Reiaren. In particular PCB126 contributed highly to the total TEQ (69-82%). In 19 of the 23 samples the calculated WHO TEQ was higher than the TEQCALUX. Using CALUX specific relative effect potencies (REPs), the levels were lower at between 77 and 292 pg/g lw in eggs from Musvær and between 55 and 223 pg/g lw in eggs from Reiaren, which was higher than the TEQCALUX in 16 of the 23 samples. However, the means of the REP values and the TEQCALUX were not significantly different. This suggests the presence of compounds that can elicit antagonist effects, with a low binding affinity to the AhR. Non-target analysis identified the presence of hexachlorobenzene (HCB) (quantified at 9.6-185 pg/g lw) but neither this compound nor high concentrations of PCB126 and non-dioxin-like PCBs could explain the differences between the calculated TEQ or REP values and the TEQCALUX. Even though, for most AhR agonists, the sensitivity of herring gulls is not known, the reported levels can be considered to represent a risk for biological effects in the developing embryo, compared to LC50 values in chicken embryos. For human consumers of herring gull eggs, these eggs contain TEQ levels up to four times higher than the maximum tolerable weekly intake. Copyright © 2015 Elsevier B.V. All rights reserved.

Xenobiotics and loss of cell adhesion drive distinct transcriptional outcomes by aryl hydrocarbon receptor signaling.

PubMed

Hao, Nan; Lee, Kian Leong; Furness, Sebastian G B; Bosdotter, Cecilia; Poellinger, Lorenz; Whitelaw, Murray L

2012-12-01

The aryl hydrocarbon receptor (AhR) is a signal-regulated transcription factor, which is canonically activated by the direct binding of xenobiotics. In addition, switching cells from adherent to suspension culture also activates the AhR, representing a nonxenobiotic, physiological activation of AhR signaling. Here, we show that the AhR is recruited to target gene enhancers in both ligand [isopropyl-2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2-yl)carbamoyl]acetate (YH439)]-treated and suspension cells, suggesting a common mechanism of target gene induction between these two routes of AhR activation. However, gene expression profiles critically differ between xenobiotic- and suspension-activated AhR signaling. Por and Cldnd1 were regulated predominantly by ligand treatments, whereas, in contrast, ApoER2 and Ganc were regulated predominantly by the suspension condition. Classic xenobiotic-metabolizing AhR targets such as Cyp1a1, Cyp1b1, and Nqo1 were regulated by both ligand and suspension conditions. Temporal expression patterns of AhR target genes were also found to vary, with examples of transient activation, transient repression, or sustained alterations in expression. Furthermore, sequence analysis coupled with chromatin immunoprecipitation assays and reporter gene analysis identified a functional xenobiotic response element (XRE) in the intron 1 of the mouse Tiparp gene, which was also bound by hypoxia-inducible factor-1α during hypoxia and features a concatemer of four XRE cores (GCGTG). Our data suggest that this XRE concatemer site concurrently regulates the expression of both the Tiparp gene and its cis antisense noncoding RNA after ligand- or suspension-induced AhR activation. This work provides novel insights into how AhR signaling drives different transcriptional programs via the ligand versus suspension modes of activation.

Different regulation of aryl hydrocarbon receptor-regulated genes in response to dioxin in undifferentiated and neuronally differentiated human neuroblastoma SH-SY5Y cells.

PubMed

Imran, Saima; Ferretti, Patrizia; Vrzal, Radim

2015-01-01

Some environmental pollutants derived from industrial processes have been suggested to be responsible for neurological impairment in children, especially in heavily polluted areas. Since these compounds are usually activators of aryl hydrocarbon receptor (AhR), it would be important to better understand the molecular pathways downstream of AhR leading to neural deficits. To this purpose, appropriate in vitro human neural model is much needed. Here we have investigated whether undifferentiated and neuronally differentiated human neuroblastoma cells, SH-SY5Y cells, can provide a suitable model for monitoring AhR activity induced by environmental pollutants, focusing on 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD), a known activator of AhR. Further characterization of differentiated SH-SY5Y showed an increase in AhRR (aryl hydrocarbon receptor repressor), no change in ARNT1 (AhR nuclear translocator 1), and a decrease in ARNT2 expression with differentiation; in contrast, AhR was undetectable in both undifferentiated and differentiated cells. Nonetheless, treatment of parental as well as differentiated SH-SY5Y cells with TCDD resulted in the induction of AhR-regulated genes, CYP1A1 and CYP1B1; AhRR expression was also affected, but to a much smaller extent. These results indicate that undifferentiated SH-SY5Y are less sensitive to TCDD than neuronally differentiated ones, suggesting a higher resistance of the undifferentiated tumor cells to toxic insults. They also suggest that TCDD in these cells may not act via direct activation of AhR that is undetectable in SH-SY5Y as well as in differentiated neurons. Hence, these cells do not provide an appropriate model for studying ligand-mediated activation of AhR.

Elucidating the Role of CD84 and AHR in Modulation of LPS-Induced Cytokines Production by Cruciferous Vegetable-Derived Compounds Indole-3-Carbinol and 3,3′-Diindolylmethane

PubMed Central

Wang, Thomas T. Y.; Pham, Quynhchi; Kim, Young S.

2018-01-01

Modulation of the immune system by cancer protective food bioactives has preventive and therapeutic importance in prostate cancer, but the mechanisms remain largely unclear. The current study tests the hypothesis that the diet-derived cancer protective compounds, indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM), affect the tumor microenvironment by regulation of inflammatory responses in monocytes and macrophages. We also ask whether I3C and DIM act through the aryl hydrocarbon (AHR)-dependent pathway or the signaling lymphocyte activation molecule (SLAM) family protein CD84-mediated pathway. The effect of I3C and DIM was examined using the human THP-1 monocytic cell in its un-differentiated (monocyte) and differentiated (macrophage) state. We observed that I3C and DIM inhibited lipopolysaccharide (LPS) induction of IL-1β mRNA and protein in the monocyte form but not the macrophage form of THP-1. Interestingly, CD84 mRNA but not protein was inhibited by I3C and DIM. AHR siRNA knockdown experiments confirmed that the inhibitory effects of I3C and DIM on IL-1β as well as CD84 mRNA are regulated through AHR-mediated pathways. Additionally, the AHR ligand appeared to differentially regulate other LPS-induced cytokines expression. Hence, cross-talk between AHR and inflammation-mediated pathways, but not CD84-mediated pathways, in monocytes but not macrophages may contribute to the modulation of tumor environments by I3C and DIM in prostate cancer. PMID:29364159

Red Clover Aryl Hydrocarbon Receptor (AhR) and Estrogen Receptor (ER) Agonists Enhance Genotoxic Estrogen Metabolism

PubMed Central

2017-01-01

Many women consider botanical dietary supplements (BDSs) as safe alternatives to hormone therapy for menopausal symptoms. However, the effect of BDSs on breast cancer risk is largely unknown. In the estrogen chemical carcinogenesis pathway, P450 1B1 metabolizes estrogens to 4-hydroxylated catechols, which are oxidized to genotoxic quinones that initiate and promote breast cancer. In contrast, P450 1A1 catalyzed 2-hydroxylation represents a detoxification pathway. The current study evaluated the effects of red clover, a popular BDS used for women’s health, and its isoflavones, biochanin A (BA), formononetin (FN), genistein (GN), and daidzein (DZ), on estrogen metabolism. The methoxy estrogen metabolites (2-MeOE1, 4-MeOE1) were measured by LC-MS/MS, and CYP1A1 and CYP1B1 gene expression was analyzed by qPCR. Nonmalignant ER-negative breast epithelial cells (MCF-10A) and ER-positive breast cancer cells (MCF-7) were derived from normal breast epithelial tissue and ER+ breast cancer tissue. Red clover extract (RCE, 10 μg/mL) and isoflavones had no effect on estrogen metabolism in MCF-10A cells. However, in MCF-7 cells, RCE treatments downregulated CYP1A1 expression and enhanced genotoxic metabolism (4-MeOE1/CYP1B1 > 2-MeOE1/CYP1A1). Experiments with the isoflavones showed that the AhR agonists (BA, FN) preferentially induced CYP1B1 expression as well as 4-MeOE1. In contrast, the ER agonists (GN, DZ) downregulated CYP1A1 expression likely through an epigenetic mechanism. Finally, the ER antagonist ICI 182,780 potentiated isoflavone-induced XRE-luciferase reporter activity and reversed GN and DZ induced downregulation of CYP1A1 expression. Overall, these studies show that red clover and its isoflavones have differential effects on estrogen metabolism in “normal” vs breast cancer cells. In breast cancer cells, the AhR agonists stimulate genotoxic metabolism, and the ER agonists downregulate the detoxification pathway. These data may suggest that especially breast

Ultraviolet B inhibition of DNMT1 activity via AhR activation dependent SIRT1 suppression in CD4+ T cells from systemic lupus erythematosus patients.

PubMed

Wu, Zhouwei; Mei, Xingyu; Ying, Zuolin; Sun, Yue; Song, Jun; Shi, Weimin

2017-06-01

Previous studies have reported that ultraviolet B (UVB) inhibits DNA methyltransferase1 (DNMT1) activity in CD4+ T cells from systemic lupus erythematosus (SLE) patients. Silent mating type information regulation 2 homolog 1 (SIRT1) is a type of Class III histone deacetylases (HDACs), and has been reported to play roles in the pathogenesis of different autoimmune diseases and can modulate DNMT1 activity. Moreover, aryl hydrocarbon receptor (AhR) has been reported to link UVB with SLE. However, the exact mechanisms by which DNMT1 activity is inhibited by UVB in lupus CD4+ T cells remain largely unknown. To elucidate the exact mechanisms by which DNMT1 activity is inhibited by UVB in lupus CD4+ T cells. Twenty-two newly diagnosed active SLE patients and 30 healthy controls were enrolled in the study. CD4+ T cells were isolated, cultured and treated. DNMT1 activity assay, quantitative real-time PCR (qRT-PCR), Western blotting, RNA interference using small interfering RNA and Chromatin Immunoprecipitation (ChIP) assay were employed. DNMT1 activity was inhibited in si-SIRT1-transfected CD4+ T cells, and increased by the established SIRT1 activator, SRT1720. Moreover, the mRNA and protein expression of SIRT1 were suppressed by UVB exposure in lupus CD4+ T cells. UVB-inhibited DNMT1 activity was reversed by SRT1720 in si-control-transfected lupus CD4+ T cells, but not in si-SIRT1-transfected lupus CD4 + T cells. Furthermore, AhR activation by VAF347 reduced the mRNA and protein expression of SIRT1. ChIP using an antibody against AhR in normal CD4+ T cells revealed a 16-fold stronger signal at the site about 1.6kb upstream from the translation start site of the SIRT1 promoter. Finally, UVB could activate AhR and inhibit the mRNA and protein expression of SIRT1. AhR knockdown abrogated the inhibition of UVB-mediated SIRT1 mRNA and protein expression and DNMT1 activity in lupus CD4+ T cells. UVB suppressed SIRT1 expression via activating AhR, and subsequently inhibited DNMT1

Studies on the Role of The Ah Receptor (AhR) on the Etiology of Breast Cancer: A Novel Idea of Identifying this Receptor as a New Therapeutic Target

DTIC Science & Technology

2010-09-01

found that the most potent phytochemical suppressors of cell proliferation of P20E cells were curcumin (10 µM approximately 80 to 90% suppression...effectiveness of a number of phytochemicals from edible plants known to block AhR in attenuating the expression of high rates of cell proliferation...selected number of those phytochemicals , by xenografting those AhR overexpressing human breast cancer cells into athymic nude mice, and by treating

Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation.

PubMed

Liu, Yuying; Liang, Xiaoyu; Dong, Wenqian; Fang, Yi; Lv, Jiadi; Zhang, Tianzhen; Fiskesund, Roland; Xie, Jing; Liu, Jinyan; Yin, Xiaonan; Jin, Xun; Chen, Degao; Tang, Ke; Ma, Jingwei; Zhang, Huafeng; Yu, Jing; Yan, Jun; Liang, Huaping; Mo, Siqi; Cheng, Feiran; Zhou, Yabo; Zhang, Haizeng; Wang, Jing; Li, Jingnan; Chen, Yang; Cui, Bing; Hu, Zhuo-Wei; Cao, Xuetao; Xiao-Feng Qin, F; Huang, Bo

2018-03-12

Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8 + T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8 + T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8 + T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications. Copyright © 2018 Elsevier Inc. All rights reserved.

Phenotype Refinement Strengthens the Association of AHR and CYP1A1 Genotype with Caffeine Consumption

PubMed Central

McMahon, George; Taylor, Amy E.; Davey Smith, George; Munafò, Marcus R.

2014-01-01

Two genetic loci, one in the cytochrome P450 1A1 (CYP1A1) and 1A2 (CYP1A2) gene region (rs2472297) and one near the aryl-hydrocarbon receptor (AHR) gene (rs6968865), have been associated with habitual caffeine consumption. We sought to establish whether a more refined and comprehensive assessment of caffeine consumption would provide stronger evidence of association, and whether a combined allelic score comprising these two variants would further strengthen the association. We used data from between 4,460 and 7,520 women in the Avon Longitudinal Study of Parents and Children, a longitudinal birth cohort based in the United Kingdom. Self-report data on coffee, tea and cola consumption (including consumption of decaffeinated drinks) were available at multiple time points. Both genotypes were individually associated with total caffeine consumption, and with coffee and tea consumption. There was no association with cola consumption, possibly due to low levels of consumption in this sample. There was also no association with measures of decaffeinated drink consumption, indicating that the observed association is most likely mediated via caffeine. The association was strengthened when a combined allelic score was used, accounting for up to 1.28% of phenotypic variance. This was not associated with potential confounders of observational association. A combined allelic score accounts for sufficient phenotypic variance in caffeine consumption that this may be useful in Mendelian randomization studies. Future studies may therefore be able to use this combined allelic score to explore causal effects of habitual caffeine consumption on health outcomes. PMID:25075865

The aryl hydrocarbon receptor and glucocorticoid receptor interact to activate human metallothionein 2A

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sato, Shoko, E-mail: satosho@rs.tus.ac.jp; Shirakawa, Hitoshi, E-mail: shirakah@m.tohoku.ac.jp; Tomita, Shuhei, E-mail: tomita@med.tottori-u.ac.jp

2013-11-15

Although the aryl hydrocarbon receptor (AHR) and glucocorticoid receptor (GR) play essential roles in mammalian development, stress responses, and other physiological events, crosstalk between these receptors has been the subject of much debate. Metallothioneins are classic glucocorticoid-inducible genes that were reported to increase upon treatment with AHR agonists in rodent tissues and cultured human cells. In this study, the mechanism of human metallothionein 2A (MT2A) gene transcription activation by AHR was investigated. Cotreatment with 3-methylcholanthrene and dexamethasone, agonists of AHR and GR respectively, synergistically increased MT2A mRNA levels in HepG2 cells. MT2A induction was suppressed by RNA interference against AHRmore » or GR. Coimmunoprecipitation experiments revealed a physical interaction between AHR and GR proteins. Moreover, chromatin immunoprecipitation assays indicated that AHR was recruited to the glucocorticoid response element in the MT2A promoter. Thus, we provide a novel mechanism whereby AHR modulates expression of human MT2A via the glucocorticoid response element and protein–protein interactions with GR. - Highlights: • Aryl hydrocarbon receptor forms a complex with glucocorticoid receptor in cells. • Human metallothionein gene is regulated by the AHR and GR interaction. • AHR–GR complex binds to glucocorticoid response element in metallothionein gene. • We demonstrated a novel transcriptional mechanism via AHR and GR interaction.« less

Battery resource assessment. Battery demands scenarios materials

NASA Astrophysics Data System (ADS)

Sullivan, D.

1980-12-01

Projections of demand for batteries and battery materials between 1980 and 2000 are presented. The estimates are based on existing predictions for the future of the electric vehicle, photovoltaic, utility load-leveling, and existing battery industry. Battery demand was first computed as kilowatt-hours of storage for various types of batteries. Using estimates for the materials required for each battery, the maximum demand that could be expected for each battery material was determined.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luo, Yueh-Hsia; Kuo, Yu-Chun; Tsai, Ming-Hsien

Exposure to environmental aryl hydrocarbon receptor (AhR) agonists, such as halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs), has great impacts on the development of various lung diseases. As emerging molecular targets for AhR agonists, cytokines may contribute to the inflammatory or immunotoxic effects of environmental AhR agonists. However, general cytokine expression may not specifically indicate environmental AhR agonist exposure. By comparing cytokine and chemokine expression profiles in human lung adenocarcinoma cell line CL5 treated with AhR agonists and the non-AhR agonist polychlorinated biphenyl (PCB) 39, we identified a target cytokine of environmental AhR agonist exposure of in the lungs.more » Thirteen cytokine and chemokine genes were altered in the AhR agonists-treated cells, but none were altered in the PCB39-treated cells. Interleukin (IL)-24 was the most highly induced gene among AhR-modulated cytokines. Cotreatment with AhR antagonist completely prevented IL-24 induction by AhR agonists in the CL5 cells. Knockdown AhR expression with short-hairpin RNA (shRNA) significantly reduced benzo[a]pyrene (BaP)-induced IL-24 mRNA levels. We further confirmed that gene transcription, but not mRNA stability, was involved in IL-24 upregulation by BaP. Particulate matter (PM) in the ambient air contains some PAHs and is reported to activate AhR. Oropharyngeal aspiration of PM significantly increased IL-24 levels in lung epithelia and in bronchoalveolar lavage fluid of mice 4 weeks after treatment. Thus, our data suggests that IL-24 is a pulmonary exposure target cytokine of environmental AhR agonists. - Graphical abstract: (A) Cytokine and chemokine gene expressions were examined in CL5 cells treated with AhR and non-AhR agonists. Thirteen cytokines and chemokines genes were altered in the AhR agonist-treated cells, but not in the non-AhR agonist-treated cells. IL-24 was the most highly induced gene among the Ah

Polychlorinated biphenyls (PCBs) contamination and aryl hydrocarbon receptor (AhR) agonist activity of Omega-3 polyunsaturated fatty acid supplements: implications for daily intake of dioxins and PCBs.

PubMed

Bourdon, J A; Bazinet, T M; Arnason, T T; Kimpe, L E; Blais, J M; White, P A

2010-11-01

Omega-3 polyunsaturated fatty acid (n-3 PUFA) rich oils derived primarily from fish are frequently consumed as supplements. Due to the tendency of persistent organic pollutants (POPs) to accumulate in exposed organisms, n-3 PUFA supplements can contain sufficient POPs to present a risk to consumers. Here we investigated PCB concentrations and aryl hydrocarbon receptor (AhR) agonist activity in 17 n-3 PUFA supplements available in Canada. PCBs ranged from <0.8 to 793 ng g(-1) oil, with salmon- and seal-derived products yielding the highest values. AhR agonist activity from a reporter gene assay ranged from 1.3 to 72.2 pg TEQ g(-1) oil, with salmon and tuna yielding the highest values. When consumed at the recommended doses and as a supplement to the average Canadian diet, seal-derived oil can contribute to exceedance of the tolerable daily intake of 20 ng PCBs kg-BW(-1)day(-1), and salmon-, tuna-, and sea herring-derived oils can contribute to exceedance of the tolerable daily intake limit of 2.3 pg TEQ kg-BW(-1)day(-1). The beneficial properties of fish and n-3 PUFA supplements, and the results of this study suggest that it is prudent to consume supplements derived from small, cold-water fatty fish. Further research will be necessary to draw firm conclusions. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.

Cyp2a5 Promoter-based Gene Reporter Assay: A Novel Design of Cell-based Bioassay for Toxicity Prediction.

PubMed

Abu-Bakar, A'edah; Hu, Hao; Lang, Matti A

2018-05-22

The murine cytochrome P450 2a5 (Cyp2a5) gene is regulated by complex interactions of various stress-activated transcription factors (TFs). Elevated Cyp2a5 transcription under chemical-induced stress conditions is achieved by interplay between the various TFs-including as aryl hydrocarbon receptor (AhR) and nuclear factor (erythroid-derived 2)-like 2 wild-type (Nrf2)-at the "stress-responding" cluster of response elements on the Cyp2a5 promoter, as well as through mRNA stabilisation mediated by interaction of the stress-activated heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) with the 3'UTR of the CYP2A5 mRNA. We design a unique toxicity pathway-based reporter assay to include regulatory regions from both the 5' and the 3' untranslated regions of Cyp2a5 in a luciferase reporter plasmid to reflect in vivo responses to chemical insult. Human breast cancer, MCF-7 cells were stably transfected with pGL4.38-Cyp2a5_Wt3k (wildtype) or mutants-pGL4.38-Cyp2a5-StREMut and pGL4.38-Cyp2a5-XREMut-reporter gene to monitor chemical-induced cellular response mediated by AhR and Nrf2 signalling. The recombinant cells were treated with representative of AhR agonist, polycyclic aromatic hydrocarbons, brominated flame retardant, fluorosurfactant, aromatic organic compound and metal, to determine sensitivity of the Cyp2a5 promoter-based gene reporter assays to chemical insults by measuring the LC 50 and EC 50 of the respective chemicals. The three assays are sensitive to sub-lethal cellular responses of chemicals, which is an ideal feature for toxicity pathway-based bioassay for toxicity prediction. The wildtype reporter responded well to chemicals that activate cross-talk between the AhR and Nrf2, whilst the mutant reporters effectively gauge cellular response driven by either Nrf2/StRE or AhR/XRE signalling. Thus, the three gene reporter assays could be used tandemly to determine the predominant toxicity pathway of a given compound. This article is protected by copyright. All

AHR-related activities in a creosote-adapted population of adult atlantic killifish, Fundulus heteroclitus, two decades post-EPA superfund status at the Atlantic Wood Site, Portsmouth, VA USA.

PubMed

Wojdylo, Josephine V; Vogelbein, Wolfgang; Bain, Lisa J; Rice, Charles D

2016-08-01

Atlantic killifish, Fundulus heteroclitus, are adapted to creosote-based PAHs at the US EPA Superfund site known as Atlantic Wood (AW) on the southern branch of the Elizabeth River, VA USA. Subsequent to the discovery of the AW population in the early 1990s, these fish were shown to be recalcitrant to CYP1A induction by PAHs under experimental conditions, and even to the time of this study, killifish embryos collected from the AW site are resistant to developmental deformities typically associated with exposure to PAHs in reference fish. Historically, however, 90 +% of the adult killifish at this site have proliferative hepatic lesions including cancer of varying severity. Several PAHs at this site are known to be ligands for the aryl hydrocarbon receptor (AHR). In this study, AHR-related activities in AW fish collected between 2011 and 2013 were re-examined nearly 2 decades after first discovery. This study shows that CYP1A mRNA expression is three-fold higher in intestines of AW killifish compared to a reference population. Using immunohistochemistry, CYP1A staining in intestines was uniformly positive compared to negative staining in reference fish. Livers of AW killifish were examined by IHC to show that CYP1A and AHR2 protein expression reflect lesions-specific patterns, probably representing differences in intrinsic cellular physiology of the spectrum of proliferative lesions comprising the hepatocarcinogenic process. We also found that COX2 mRNA expression levels were higher in AW fish livers compared to those in the reference population, suggesting a state of chronic inflammation. Overall, these findings suggest that adult AW fish are responsive to AHR signaling, and do express CYP1A and AHR2 proteins in intestines at a level above what was observed in the reference population. Copyright © 2016 Elsevier B.V. All rights reserved.

AHR-related Activities in a Creosote-Adapted Population of Adult Atlantic Killifish, Fundulus heteroclitus, Two Decades Post-EPA Superfund Status at the Atlantic Wood Site, Portsmouth, VA USA

PubMed Central

Wojdylo, Josephine V.; Vogelbein, Wolfgang; Bain, Lisa J.; Rice, Charles D.

2016-01-01

Atlantic killifish, Fundulus heteroclitus, are adapted to creosote-based PAHs at the US EPA Superfund site known as Atlantic Wood (AW) on the southern branch of the Elizabeth River, VA USA. Subsequent to the discovery of the AW population in the early 1990s, these fish were shown to be recalcitrant to CYP1A induction by PAHs under experimental conditions, and even to the time of this study, killifish embryos collected from the AW site are resistant to developmental deformities typically associated with exposure to PAHs in reference fish. Historically, however, 90+% of the adult killifish at this site have proliferative hepatic lesions including cancer of varying severity. Several PAHs at this site are known to be ligands for the aryl hydrocarbon receptor (AHR). In this study, AHR-related activities in AW fish collected between 2011–2013 were re-examined nearly 2 decades after first discovery. This study shows that CYP1A mRNA expression is three-fold higher in intestines of AW killifish compared to a reference population. Using immunohistochemistry, CYP1A staining in intestines was uniformly positive compared to negative staining in reference fish. Livers of AW killifish were examined by IHC to show that CYP1A and AHR2 protein expression reflect lesions-specific patterns, probably representing differences in intrinsic cellular physiology of the spectrum of proliferative lesions comprising the hepatocarcinogenic process. We also found that COX2 mRNA expression levels were higher in AW fish livers compared to those in the reference population, suggesting a state of chronic inflammation. Overall, these findings suggest that adult AW fish are responsive to AHR signaling, and do express CYP1A and AHR2 proteins in intestines at a level above what was observed in the reference population. PMID:27262937

Polymorphisms in aryl hydrocarbon receptor gene are associated with idiopathic male factor infertility.

PubMed

Safarinejad, Mohammad Reza; Shafiei, Nayyer; Safarinejad, Saba

2013-12-01

We wanted to determine whether genetic polymorphisms of aryl hydrocarbon receptor (AhR) gene are associated with susceptibility to male infertility. This study comprised 176 men with idiopathic infertility and 352 healthy fertile men who served as controls. Seven single-nucleotide polymorphisms (SNPs) of the AhR gene (rs2066853, rs1476080, rs10250822, rs10247158, rs2282885, rs6960165, and rs7811989) were selected and genotyped by the polymerase chain reaction-restriction fragment length polymorphism analysis. The serum levels of reproductive and thyroid hormones and inhibin B were also measured. After multiple regression analysis, 2 of the 7 studied SNPs were significantly associated with the occurrence of male infertility. Men with rs2066853 AA genotype had 33% decreased risk of being infertile (odds ratio [OR] = 0.67, 95% confidence interval [CI]: 0.46-0.87; P = .003). The C allele of rs2282885 was significantly associated with infertility risk, with an OR of 2.14 (95% CI: 1.64-3.72) for heterozygotes and 3.54 (95% CI: 2.25-5.84) for homozygotes. When haplotypes were composed of 7 AhR SNP sites, patients with AACACAG haplotype harbored more than 75% decreased risk of being infertile (OR = 0.21, 95% CI: 0.11-0.32; P = .001). Conversely, carriers of the AACACGA haplotype had more than 12-fold increased risk of being infertile (OR = 12.62, 95% CI: 2.77-52.74; P = .00001). Homozygosity for the rs2066853 A allele and rs2282885 C allele decreases and increases the risk of developing male infertility, respectively.

Aryl hydrocarbon receptor-induced adrenomedullin mediates cigarette smoke carcinogenicity in humans and mice

PubMed Central

Portal-Nuñez, Sergio; Shankavaram, Uma; Rao, Mahadev; Datrice, Nicole; Scott, Atay; Aparicio, Marta; Camphausen, Kevin A.; Fernández-Salguero, Pedro M.; Chang, Han; Lin, Pinpin; Schrump, David S.; Garantziotis, Stavros; Cuttitta, Frank; Zudaire, Enrique

2015-01-01

Cigarette smoke (CS) is a leading cause of death worldwide. The aryl hydrocarbon receptor (AHR) is partially responsible for tobacco-induced carcinogenesis although the underlying mechanisms involving early effector genes have yet to be determined. Here, we report that adrenomedullin (ADM) significantly contributes to the carcinogenicity of tobacco activated AHR. CS and AHR activating ligands induced ADM in vitro and in vivo but not in AHR-deficient fibroblasts and mice. Ectopic transfection of AHR rescued ADM expression in AHR−/− fibroblasts while AHR blockage with siRNA in wild type cells significantly decreased ADM expression. AHR regulates ADM expression through two intronic xenobiotic response elements located close to the start codon in the ADM gene. Using tissue microarrays we showed that ADM and AHR were coupregulated in lung tumor biopsies from smoker patients. Microarray metaanalysis of 304 independent microarray experiments showed that ADM is elevated in smokers and smokers with cancer. Additionally, ADM coassociated with a subset of AHR responsive genes and efficiently differentiated patients with lung cancer from non-smokers. In a novel preclinical model of CS-induced tumor progression, host exposure to CS extracts significantly elevated tumor ADM while systemic treatment with the ADM antagonist NSC16311 efficiently blocked tobacco-induced tumor growth. In conclusion, ADM significantly contributes the carcinogenic effect of AHR and tobacco combustion products. We suggest that therapeutics targeting the AHR/ADM axis may be of clinical relevance in the treatment of tobacco-induced pulmonary malignancies. PMID:22993405

Dihydromethysticin (DHM) Blocks Tobacco Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-Induced O6-Methylguanine in a Manner Independent of the Aryl Hydrocarbon Receptor (AhR) Pathway in C57BL/6 Female Mice.

PubMed

Narayanapillai, Sreekanth C; Lin, Shang-Hsuan; Leitzman, Pablo; Upadhyaya, Pramod; Baglole, Carolyn J; Xing, Chengguo

2016-11-21

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a key carcinogen responsible for tobacco smoke-induced lung carcinogenesis. Among the types of DNA damage caused by NNK and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), O 6 -methylguanine (O 6 -mG) is likely the most carcinogen in A/J mice. Results of our previous studies showed that levels of O 6 -mG and other types of NNAL-derived DNA damage were preferentially reduced in the lung of female A/J mice upon dietary treatment with dihydromethysticin (DHM), a promising lung cancer chemopreventive agent from kava. Such a differential blockage may be mediated via an increased level of NNAL glucuronidation, thereby leading to its detoxification. The potential of the aryl hydrocarbon receptor (AhR) as an upstream target of DHM mediating these events was evaluated herein using Ahr +/- and Ahr -/- C57BL/6 female mice because DHM was reported as an AhR agonist. DHM (0.05, 0.2, and 1.0 mg/g of diet) and dihydrokavain (DHK, an inactive analogue, 1.0 mg/g of diet) were given to mice for 7 days, followed by a single intraperitoneal dose of NNK at 100 mg/kg of body weight. The effects of DHM on the amount of O 6 -mG in the lung, on the urinary ratio of glucuronidated NNAL (NNAL-Gluc) and free NNAL, and on CYP1A1/2 activity in the liver microsomes were analyzed. As observed in A/J mice, DHM treatment significantly and dose-dependently reduced the level of O 6 -mG in the target lung tissue, but there were no significant differences in O 6 -mG reduction between mice from Ahr +/- and Ahr -/- backgrounds. Similarly, in both strains, DHM at 1 mg/g of diet significantly increased the urinary ratio of NNAL-Gluc to free NNAL and CYP1A1/2 enzymatic activity in liver with no changes detected at lower DHM dosages. Because none of these effects of DHM were dependent on Ahr status, AhR clearly is not the upstream target for DHM.

Comparative Toxicogenomic Responses to the Flame Retardant mITP in Developing Zebrafish.

PubMed

Haggard, Derik E; Das, Siba R; Tanguay, Robert L

2017-02-20

Monosubstituted isopropylated triaryl phosphate (mITP) is a major component of Firemaster 550, an additive flame retardant mixture commonly used in polyurethane foams. Developmental toxicity studies in zebrafish established mITP as the most toxic component of FM 550, which causes pericardial edema and heart looping failure. Mechanistic studies showed that mITP is an aryl hydrocarbon receptor (AhR) ligand; however, the cardiotoxic effects of mITP were independent of the AhR. We performed comparative whole genome transcriptomics in wild-type and ahr2 hu3335 zebrafish, which lack functional ahr2, to identify transcriptional signatures causally involved in the mechanism of mITP-induced cardiotoxicity. Regardless of ahr2 status, mITP exposure resulted in decreased expression of transcripts related to the synthesis of all-trans-retinoic acid and a host of Hox genes. Clustered gene ontology enrichment analysis showed unique enrichment in biological processes related to xenobiotic metabolism and response to external stimuli in wild-type samples. Transcript enrichments overlapping both genotypes involved the retinoid metabolic process and sensory/visual perception biological processes. Examination of the gene-gene interaction network of the differentially expressed transcripts in both genetic backgrounds demonstrated a strong AhR interaction network specific to wild-type samples, with overlapping genes regulated by retinoic acid receptors (RARs). A transcriptome analysis of control ahr2-null zebrafish identified potential cross-talk among AhR, Nrf2, and Hif1α. Collectively, we confirmed that mITP is an AhR ligand and present evidence in support of our hypothesis that mITP's developmental cardiotoxic effects are mediated by inhibition at the RAR level.

Association of IL-13 gene polymorphisms with airway hyperresponsiveness in a Japanese adult asthmatic population.

PubMed

Utsumi, Yu; Sasaki, Nobuhito; Nagashima, Hiromi; Suzuki, Naomi; Nakamura, Yutaka; Yamashita, Masahiro; Kobayashi, Hitoshi; Yamauchi, Kohei

2013-09-01

A single nucleotide polymorphism (SNP; rs20541) in the IL-13 gene has been recognized as a risk factor for asthma. This SNP causes Arg to Gln (Q) substitution at position 110 in the mature IL-13 protein. We have recently showed that FEV1 in asthmatics with the Q110 variant of IL-13 declined faster, and progressive airway remodeling was observed in these subjects (Wynn, 2003 [1]). However, the effects of the IL-13 variant on airway hyperresponsiveness (AHR) remain to be elucidated. We analyzed the relationship between SNP rs20541 in IL-13 and AHR in asthmatics. We recruited 182 asthmatics who visited the asthma outpatient clinic at Iwate Medical University Hospital from 2006 to 2011. Subjects were genotyped for rs20541. Asthma severity, atopic status, age of asthma onset, serum IgE concentration, AHR, and pulmonary function were studied in these subjects. AHR was measured using the continuous methacholine inhalation method (Astograph; Chest; Tokyo, Japan). Genotyping of rs20541 revealed 26 A/A, 77 A/G, and 79 G/G patient genotypes. The D min (U) of the 3 genotypes was 1.17±0.300 in A/A, 1.99±0.35 in A/G, and 2.85±0.39 in G/G. The D min in the 3 genotypes was significantly different. Spirometric data revealed that % FEV1 and % FEF75 were significantly different among the 3 groups of IL-13 genotypes, whereas no significant differences were observed in therapeutic steps, atopic status, house dust mite sensitization, or serum IgE concentration. The SNP rs20541 in IL-13 was associated with AHR in Japanese adult asthmatics. Copyright © 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

29 CFR 1926.441 - Batteries and battery charging.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 8 2010-07-01 2010-07-01 false Batteries and battery charging. 1926.441 Section 1926.441... for Special Equipment § 1926.441 Batteries and battery charging. (a) General requirements—(1) Batteries of the unsealed type shall be located in enclosures with outside vents or in well ventilated rooms...

29 CFR 1926.441 - Batteries and battery charging.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 8 2014-07-01 2014-07-01 false Batteries and battery charging. 1926.441 Section 1926.441... for Special Equipment § 1926.441 Batteries and battery charging. (a) General requirements—(1) Batteries of the unsealed type shall be located in enclosures with outside vents or in well ventilated rooms...

29 CFR 1926.441 - Batteries and battery charging.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 8 2011-07-01 2011-07-01 false Batteries and battery charging. 1926.441 Section 1926.441... for Special Equipment § 1926.441 Batteries and battery charging. (a) General requirements—(1) Batteries of the unsealed type shall be located in enclosures with outside vents or in well ventilated rooms...

29 CFR 1926.441 - Batteries and battery charging.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 29 Labor 8 2012-07-01 2012-07-01 false Batteries and battery charging. 1926.441 Section 1926.441... for Special Equipment § 1926.441 Batteries and battery charging. (a) General requirements—(1) Batteries of the unsealed type shall be located in enclosures with outside vents or in well ventilated rooms...

29 CFR 1926.441 - Batteries and battery charging.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 29 Labor 8 2013-07-01 2013-07-01 false Batteries and battery charging. 1926.441 Section 1926.441... for Special Equipment § 1926.441 Batteries and battery charging. (a) General requirements—(1) Batteries of the unsealed type shall be located in enclosures with outside vents or in well ventilated rooms...

Biotransformation in the zebrafish embryo -temporal gene transcription changes of cytochrome P450 enzymes and internal exposure dynamics of the AhR binding xenobiotic benz[a]anthracene.

PubMed

Kühnert, Agnes; Vogs, Carolina; Seiwert, Bettina; Aulhorn, Silke; Altenburger, Rolf; Hollert, Henner; Küster, Eberhard; Busch, Wibke

2017-11-01

Not much is known about the biotransformation capability of zebrafish (Danio rerio) embryos. For understanding possible toxicity differences to adult fish, it might be crucial to understand the biotransformation of chemicals in zebrafish embryos i.e. as part of toxicokinetics. The biotransformation capabilities were analysed for two different stages of zebrafish embryos in conjunction with the internal concentrations of a xenobiotic. Zebrafish embryos of the late cleavage/early blastula period (2-26 hpf) and the early pharyngula period (26-50 hpf) were exposed for 24 h to the AhR binding compound benz[a]anthracene (BaA). Time dependent changes in cyp transcription (cyp1a, cyp1b1, cyp1c1 and cyp1c2) as well as concentration & time-dependent courses of BaA in the fish embryo and the exposure medium were analysed. Additionally, the CYP mediated formation of biotransformation products was investigated. We found correlations between transcriptional responses and the internal concentration for both exposure types. These correlations were depending on the start of the exposure i.e. the age of the exposed embryo. While no significant induction of the examined gene transcripts was observed in the first 12 h of exposure beginning in the blastula period a correlation was apparent when exposure started later i.e. in the pharyngula period. A significant induction of cyp1a was detected already after 1.5 h of BaA exposure. Gene transcripts for cyp1b1, cyp1c1 and cyp1c2 showed expressions distinctly different from cyp1a and were, in general, less inducible by BaA in both exposure windows. The toxicokinetic analysis showed that the biotransformation capability was fivefold higher in the older fish embryos. Biotransformation products of phase I reactions were found between 32 hpf and 50 hpf and were tentatively identified as benz[a]anthracene-phenol and benz[a]anthracene-dihydrodiol-epoxide. In conclusion, not only duration but also onset of exposure in relation to the

Batteries: Overview of Battery Cathodes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Doeff, Marca M

2010-07-12

The very high theoretical capacity of lithium (3829 mAh/g) provided a compelling rationale from the 1970's onward for development of rechargeable batteries employing the elemental metal as an anode. The realization that some transition metal compounds undergo reductive lithium intercalation reactions reversibly allowed use of these materials as cathodes in these devices, most notably, TiS{sub 2}. Another intercalation compound, LiCoO{sub 2}, was described shortly thereafter but, because it was produced in the discharged state, was not considered to be of interest by battery companies at the time. Due to difficulties with the rechargeability of lithium and related safety concerns, however,more » alternative anodes were sought. The graphite intercalation compound (GIC) LiC{sub 6} was considered an attractive candidate but the high reactivity with commonly used electrolytic solutions containing organic solvents was recognized as a significant impediment to its use. The development of electrolytes that allowed the formation of a solid electrolyte interface (SEI) on surfaces of the carbon particles was a breakthrough that enabled commercialization of Li-ion batteries. In 1990, Sony announced the first commercial batteries based on a dual Li ion intercalation system. These devices are assembled in the discharged state, so that it is convenient to employ a prelithiated cathode such as LiCoO{sub 2} with the commonly used graphite anode. After charging, the batteries are ready to power devices. The practical realization of high energy density Li-ion batteries revolutionized the portable electronics industry, as evidenced by the widespread market penetration of mobile phones, laptop computers, digital music players, and other lightweight devices since the early 1990s. In 2009, worldwide sales of Li-ion batteries for these applications alone were US$ 7 billion. Furthermore, their performance characteristics (Figure 1) make them attractive for traction applications such as

An Interaction of LPS and RSV Infection in Augmenting the AHR and Airway Inflammation in Mice.

PubMed

Zhou, Na; Li, Wei; Ren, Luo; Xie, Xiaohong; Liu, Enmei

2017-10-01

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection (LRTI) in children under 5 years of age, especially infants with severe bronchiolitis. Our preliminary clinical experiments showed that bacterial colonization was commonly observed in children with virus-induced wheezing, particularly in those with recurrent wheezing, suggesting that bacterial colonization with an accompanying viral infection may contribute to disease severity. In most cases, RSV-infected infants were colonized with pathogenic bacteria (mainly Gram-negative bacteria). LPS is the main component of Gram-negative bacteria and acts as a ligand for Toll-like receptor 4 (TLR4). Relevant studies have reported that the TLR family is crucial in mediating the link between viral components and immunologic responses to infection. Of note, TLR4 activation has been associated with disease severity during RSV infection. In the present study, we identified that LPS aggravated RSV-induced AHR and airway inflammation in BALB/c mice using an RSV coinfection model. We found that the airway inflammatory cells and cytokines present in BALF and TRIF in lung tissue play a role in inducing AHR and airway inflammation upon RSV and bacteria coinfection, which might occur through the TRIF-MMP-9-neutrophil-MMP-9 signalling pathway. These results may aid in the development of novel treatments and improve vaccine design.

USE OF THE TEQ MODEL FOR ASSESSING AHR MEDIATED TOXICITY RISKS TO POPULATIONS OF LAKE TROUT AND OTHER SPECIES IN LAKE ONTARIO

EPA Science Inventory

The toxicity equivalence (TEQ) model for assessing aryl hydrocarbon receptor (AHR) mediated toxicity risks associated with polyhalogenated aromatic chemicals structurally similar to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been applied to human health risks for more than 15...

Hepatic expression patterns of aryl hydrocarbon receptor, pregnane X receptor, two cytochrome P450s and five phase II metabolism genes responsive to 17alpha-methyltestosterone in rare minnow Gobiocypris rarus.

PubMed

Gao, Jiancao; Liu, Shaozhen; Zhang, Yingying; Yuan, Cong; Yang, Yanping; Wang, Zaizhao

2014-05-01

17Alpha-methyltestosterone (MT), a synthetic androgen, is widely used in aquaculture. Aquatic organisms can receive continuous exposure to residual MT throughout their lives. Aiming to evaluate the effects of MT on genes involved in biotransformation pathway, meanwhile attempting to unravel the MT metabolic pathway at the transcriptional level in fish, here we isolated the cDNAs of previously unreported AHR2, Sult1 st1, Ugt2a1 and Ugt2b6 in rare minnow, and predominantly investigated the hepatic transcriptional patterns of AHR2, PXR and five biotransformation genes after MT exposure in both genders adult rare minnow Gobiocypris rarus. The present findings suggest that AHR2 and PXR should play important roles in regulating biotransformation enzymes related to MT catabolism, moreover, CYP1A, CYP3A, SULT1 ST4, SULT1 ST6 and UGT2A1 may play certain roles in catabolism of MT in adult G. rarus. Additionally, UGT2A1 may make greater contribution than SULT1 ST4 and SULT1 ST6 in MT catabolism in males. Copyright © 2014 Elsevier B.V. All rights reserved.

Smart battery controller for lithium sulfur dioxide batteries

NASA Astrophysics Data System (ADS)

Atwater, Terrill; Bard, Arnold; Testa, Bruce; Shader, William

1992-08-01

Each year, the U.S. Army purchases millions of lithium sulfur dioxide batteries for use in portable electronics equipment. Because of their superior rate capability and service life over a wide variety of conditions, lithium batteries are the power source of choice for military equipment. There is no convenient method of determining the available energy remaining in partially used lithium batteries; hence, users do not take full advantage of all the available battery energy. Currently, users replace batteries before each mission, which leads to premature disposal, and results in the waste of millions of dollars in battery energy every year. Another problem of the lithium battery is that it is necessary to ensure complete discharge of the cells when the useful life of the battery has been expended, or when a hazardous condition exists; a hazardous condition may result in one or more of the cells venting. The Electronics Technology and Devices Laboratory has developed a working prototype of a smart battery controller (SBC) that addresses these problems.

Battery Cell Balancing Optimisation for Battery Management System

NASA Astrophysics Data System (ADS)

Yusof, M. S.; Toha, S. F.; Kamisan, N. A.; Hashim, N. N. W. N.; Abdullah, M. A.

2017-03-01

Battery cell balancing in every electrical component such as home electronic equipment and electric vehicle is very important to extend battery run time which is simplified known as battery life. The underlying solution to equalize the balance of cell voltage and SOC between the cells when they are in complete charge. In order to control and extend the battery life, the battery cell balancing is design and manipulated in such way as well as shorten the charging process. Active and passive cell balancing strategies as a unique hallmark enables the balancing of the battery with the excellent performances configuration so that the charging process will be faster. The experimental and simulation covers an analysis of how fast the battery can balance for certain time. The simulation based analysis is conducted to certify the use of optimisation in active or passive cell balancing to extend battery life for long periods of time.

Battery charging control methods, electric vehicle charging methods, battery charging apparatuses and rechargeable battery systems

DOEpatents

Tuffner, Francis K [Richland, WA; Kintner-Meyer, Michael C. W. [Richland, WA; Hammerstrom, Donald J [West Richland, WA; Pratt, Richard M [Richland, WA

2012-05-22

Battery charging control methods, electric vehicle charging methods, battery charging apparatuses and rechargeable battery systems. According to one aspect, a battery charging control method includes accessing information regarding a presence of at least one of a surplus and a deficiency of electrical energy upon an electrical power distribution system at a plurality of different moments in time, and using the information, controlling an adjustment of an amount of the electrical energy provided from the electrical power distribution system to a rechargeable battery to charge the rechargeable battery.

An Advanced Battery Management System for Lithium Ion Batteries

DTIC Science & Technology

2011-08-01

MINI-SYMPOSIUM AUGUST 9-11 DEARBORN, MICHIGAN AN ADVANCED BATTERY MANAGEMENT SYSTEM FOR LITHIUM ION BATTERIES Bruce Pilvelait, Ph.D...COVERED - 4. TITLE AND SUBTITLE An Advanced Battery Management System for Lithium Ion Batteries 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c...Management System for Lithium Ion Batteries Page 2 of 7 Figure 1: BMS architecture for a 24 VDC lithium-ion Silent Watch battery pack

Moderate temperature rechargeable sodium batteries

NASA Technical Reports Server (NTRS)

Abraham, K. M.; Rupich, M. W.; Pitts, L.; Elliott, J. E.

1983-01-01

Cells utilizing the organic electrolyte, NaI in triglyme, operated at approx. 130 C with Na(+) - intercalating cathodes. However, their rate and stability were inadequate. NaAlCl4 was found to be a highly useful electrolyte for cell operation at 165-190 C. Na(+) intercalating chalcogenides reacted with NaAlCl4 during cycling to form stable phases. Thus, VS2 became essentially VS2Cl, with reversible capacity of approx 2.8 e(-)/V, and a mid-discharge voltage of approx 2.5V and 100 deep discharge cycles were readily achieved. A positive electrode consisting of VCl3 and S plus NaAlCl4 was subjected to deep-discharge cycles 300 times and it demonstrated identity with the in-situ-formed BSxCly cathode. NiS2 and NiS which are not Na(+)-intercalating structures formed highly reversible electrodes in NaAlCl4. The indicated discharge mechanism implies a theoretical capacity 4e(-)/Ni for NiS2 and 2e(-)/Ni for NiS. The mid-discharge potentials are, respectively, 2.4V and 2.1V. A Na/NiS2 cell cycling at a C/5 rate has exceeded 500 deep discharge cycles with 2.5e(-)/Ni average utilization. A 4 A-hr nominal capacity prototype Na/NiS2 cell was tested at 190 C. It was voluntarily terminated after 80 cycles. Further development, particularly of cathode structure and hardware should produce a battery capable of at least 50-W-hr/lb and more than 1000 cycles.

Fault-tolerant battery system employing intra-battery network architecture

DOEpatents

Hagen, Ronald A.; Chen, Kenneth W.; Comte, Christophe; Knudson, Orlin B.; Rouillard, Jean

2000-01-01

A distributed energy storing system employing a communications network is disclosed. A distributed battery system includes a number of energy storing modules, each of which includes a processor and communications interface. In a network mode of operation, a battery computer communicates with each of the module processors over an intra-battery network and cooperates with individual module processors to coordinate module monitoring and control operations. The battery computer monitors a number of battery and module conditions, including the potential and current state of the battery and individual modules, and the conditions of the battery's thermal management system. An over-discharge protection system, equalization adjustment system, and communications system are also controlled by the battery computer. The battery computer logs and reports various status data on battery level conditions which may be reported to a separate system platform computer. A module transitions to a stand-alone mode of operation if the module detects an absence of communication connectivity with the battery computer. A module which operates in a stand-alone mode performs various monitoring and control functions locally within the module to ensure safe and continued operation.

Dibutyl Phthalate (DBP)-Induced Apoptosis and Neurotoxicity are Mediated via the Aryl Hydrocarbon Receptor (AhR) but not by Estrogen Receptor Alpha (ERα), Estrogen Receptor Beta (ERβ), or Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Mouse Cortical Neurons.

PubMed

Wójtowicz, Anna K; Szychowski, Konrad A; Wnuk, Agnieszka; Kajta, Małgorzata

2017-01-01

Dibutyl phthalate (di-n-butyl phthalate, DBP) is one of the most commonly used phthalate esters. DBP is widely used as a plasticizer in a variety of household industries and consumer products. Because phthalates are not chemically bound to products, they can easily leak out to enter the environment. DBP can pass through the placental and blood-brain barriers due to its chemical structure, but little is known about its mechanism of action in neuronal cells. This study demonstrated the toxic and apoptotic effects of DBP in mouse neocortical neurons in primary cultures. DBP stimulated caspase-3 and LDH activities as well as ROS formation in a concentration (10 nM-100 µM) and time-dependent (3-48 h) manner. DBP induced ROS formation at nanomolar concentrations, while it activated caspase-3 and LDH activities at micromolar concentrations. The biochemical effects of DBP were accompanied by decreased cell viability and induction of apoptotic bodies. Exposure to DBP reduced Erα and Pparγ mRNA expression levels, which were inversely correlated with protein expression of the receptors. Treatment with DBP enhanced Ahr mRNA expression, which was reflected by the increased AhR protein level observed at 3 h after exposure. ERα, ERβ, and PPARγ antagonists stimulated DBP-induced caspase-3 and LDH activities. AhR silencing demonstrated that DBP-induced apoptosis and neurotoxicity are mediated by AhR, which is consistent with the results from DBP-induced enhancement of AhR mRNA and protein expression. Our study showed that AhR is involved in DBP-induced apoptosis and neurotoxicity, while the ERs and PPARγ signaling pathways are impaired by the phthalate.

Button batteries

MedlinePlus

Swallowing batteries ... These devices use button batteries: Calculators Cameras Hearing aids Penlights Watches ... If a person puts the battery up their nose and breathes it further in, ... problems Cough Pneumonia (if the battery goes unnoticed) ...

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hwang, Hye Jin

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor within the Per-Arnt-Sim (PAS) domain superfamily. Exposure to the most potent AHR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is associated with various pathological effects including metabolic syndrome. While research over the last several years has demonstrated a role for oxidative stress and metabolic dysfunction in AHR-dependent TCDD-induced toxicity, the role of the mitochondria in this process has not been fully explored. Our previous research suggested that a portion of the cellular pool of AHR could be found in the mitochondria (mitoAHR). Using a protease protection assay with digitonin extraction, we have now shownmore » that this mitoAHR is localized to the inter-membrane space (IMS) of the organelle. TCDD exposure induced a degradation of mitoAHR similar to that of cytosolic AHR. Furthermore, siRNA-mediated knockdown revealed that translocase of outer-mitochondrial membrane 20 (TOMM20) was involved in the import of AHR into the mitochondria. In addition, TCDD altered cellular respiration in an AHR-dependent manner to maintain respiratory efficiency as measured by oxygen consumption rate (OCR). Stable isotope labeling by amino acids in cell culture (SILAC) identified a battery of proteins within the mitochondrial proteome influenced by TCDD in an AHR-dependent manner. Among these, 17 proteins with fold changes ≥ 2 are associated with various metabolic pathways, suggesting a role of mitochondrial retrograde signaling in TCDD-mediated pathologies. Collectively, these studies suggest that mitoAHR is localized to the IMS and AHR-dependent TCDD-induced toxicity, including metabolic dysfunction, wasting syndrome, and hepatic steatosis, involves mitochondrial dysfunction. - Highlights: • The mitoAHR is localized in the mitochondrial intermembrane space. • TOMM20 participates in mitoAHR translocation. • AHR contributes to the maintenance of respiratory control ratio

Battery resource assessment. Subtask 2.5: Battery manufacturing capability recycling of battery materials

NASA Astrophysics Data System (ADS)

Pemsler, P.

1981-02-01

Studies were conducted on the recycling of advanced battery system components for six different battery systems. These include: nickel/zinc, nickel/iron, zinc/chlorine, zinc/bromine, sodium/sulfur, and lithium-aluminum/iron sulfide. For each battery system, one or more processes were developed which would permit recycling of the major or active materials. Each recycle process was designed to produce a product material which can be used directly as a raw material by the battery manufacturer. Metal recoverabilities are in the range of 93 to 95% for all processes. In each case, capital and operating costs were developed for a recycling plant which processes 100,000 electric vehicle batteries per year.

A Model for Aryl Hydrocarbon Receptor-Activated Gene Expression Shows Potency and Efficacy Changes and Predicts Squelching Due to Competition for Transcription Co-Activators

PubMed Central

Simon, Ted W.; Budinsky, Robert A.; Rowlands, J. Craig

2015-01-01

A stochastic model of nuclear receptor-mediated transcription was developed based on activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and subsequent binding the activated AHR to xenobiotic response elements (XREs) on DNA. The model was based on effects observed in cells lines commonly used as in vitro experimental systems. Following ligand binding, the AHR moves into the cell nucleus and forms a heterodimer with the aryl hydrocarbon nuclear translocator (ARNT). In the model, a requirement for binding to DNA is that a generic coregulatory protein is subsequently bound to the AHR-ARNT dimer. Varying the amount of coregulator available within the nucleus altered both the potency and efficacy of TCDD for inducing for transcription of CYP1A1 mRNA, a commonly used marker for activation of the AHR. Lowering the amount of available cofactor slightly increased the EC50 for the transcriptional response without changing the efficacy or maximal response. Further reduction in the amount of cofactor reduced the efficacy and produced non-monotonic dose-response curves (NMDRCs) at higher ligand concentrations. The shapes of these NMDRCs were reminiscent of the phenomenon of squelching. Resource limitations for transcriptional machinery are becoming apparent in eukaryotic cells. Within single cells, nuclear receptor-mediated gene expression appears to be a stochastic process; however, intercellular communication and other aspects of tissue coordination may represent a compensatory process to maintain an organism’s ability to respond on a phenotypic level to various stimuli within an inconstant environment. PMID:26039703

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Ya-Hsin; Huang, Su-Chin; Lin, Chun-Ju

Environmental cigarette smoke has been suggested to promote lung adenocarcinoma progression through aryl hydrocarbon receptor (AhR)-signaled metabolism. However, whether AhR facilitates metabolic activation or detoxification in exposed adenocarcinoma cells remains ambiguous. To address this question, we have modified the expression level of AhR in two human lung adenocarcinoma cell lines and examined their response to an extract of cigarette sidestream smoke particulates (CSSP). We found that overexpression of AhR in the CL1-5 cell line reduced CSSP-induced ROS production and oxidative DNA damage, whereas knockdown of AhR expression increased ROS level in CSSP-exposed H1355 cells. Oxidative stress sensor Nrf2 and itsmore » target gene NQO1 were insensitive to AhR expression level and CSSP treatment in human lung adenocarcinoma cells. In contrast, induction of AhR expression concurrently increased mRNA expression of xenobiotic-metabolizing genes CYP1B1, UGT1A8, and UGT1A10 in a ligand-independent manner. It appeared that AhR accelerated xenobiotic clearing and diminished associated oxidative stress by coordinate regulation of a set of phase I and II metabolizing genes. However, the AhR-signaled protection could not shield cells from constant oxidative stress. Prolonged exposure to high concentrations of CSSP induced G0/G1 cell cycle arrest via the p53–p21–Rb1 signaling pathway. Despite no effect on DNA repair rate, AhR facilitated the recovery of cells from growth arrest when CSSP exposure ended. AhR-overexpressing lung adenocarcinoma cells exhibited an increased anchorage-dependent and independent proliferation when recovery from exposure. In summary, our data demonstrated that AhR protected lung adenocarcinoma cells against CSSP-induced oxidative stress and promoted post-exposure clonogenicity. -- Highlights: ► AhR expression level influences cigarette sidestream smoke-induced ROS production. ► AhR reduces oxidative stress by coordinate regulation of

Loss of aryl hydrocarbon receptor promotes gene changes associated with premature hematopoietic stem cell exhaustion and development of a myeloproliferative disorder in aging mice.

PubMed

Singh, Kameshwar P; Bennett, John A; Casado, Fanny L; Walrath, Jason L; Welle, Stephen L; Gasiewicz, Thomas A

2014-01-15

Loss of immune function and increased hematopoietic disease are among the most clinically significant consequences of aging. Hematopoietic stem cells (HSCs) from mice lacking aryl hydrocarbon receptor (AhR) have high rates of cell division. Studies were designed to test the hypothesis that aging AhR-null allele (AhR-KO) mice develop premature HSC exhaustion, and changes leading to hematological disease. Compared to wild-type, aging AhR-KO mice showed a decreased survival rate, splenomegaly, increased circulating white blood cells, hematopoietic cell accumulation in tissues, and anemia. Analysis of bone marrow indicated increased numbers of stem/progenitor and lineage-committed cells, but decreased erythroid progenitors. There was also decreased self-renewal capacity of HSCs determined by competitive repopulation and serial transplantation. HSCs also showed increased levels of reactive oxygen species (ROS), Ki-67, and γ-H2A.X, but decreased p16(Ink4a). Splenic cells from aging KO mice had abnormal expression of genes, including Gata-1, Sh2d3c, Gfi-1, p21, and c-myc, involved in trafficking and associated with leukemia. HSCs from AhR-KO mice had gene changes related to HSC maintenance and consistent with phenotype observed. The most prominent gene changes (overexpression of Srpk2, Creb1, Hes1, mtor, pdp1) have been associated with HSC hyperproliferation, leukemia, and accelerated aging. Pathway analyses also indicated an enrichment of genes associated with oxidative stress, acute myelogenous leukemia, aging, and heat shock response, and the β-catenin/Wnt pathways. These data indicate that loss of AhR and associated changes in multiple signaling pathways promote premature HSC exhaustion and development of a myeloproliferative disorder. They also implicate a critical role of the AhR in the regulation of HSCs.

Hypoxia perturbs aryl hydrocarbon receptor signaling and CYP1A1 expression induced by PCB 126 in human skin and liver-derived cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vorrink, Sabine U.; Department of Radiation Oncology, The University of Iowa, Iowa City, IA; Severson, Paul L.

2014-02-01

The aryl hydrocarbon receptor (AhR) is an important mediator of toxic responses after exposure to xenobiotics including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like polychlorinated biphenyls (PCBs). Activation of AhR responsive genes requires AhR dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), a heterodimeric partner also shared by the hypoxia-inducible factor-1α (HIF-1α) protein. TCDD-stimulated AhR transcriptional activity can be influenced by hypoxia; however, it less well known whether hypoxia interferes with AhR transcriptional transactivation in the context of PCB-mediated AhR activation in human cells. Elucidation of this interaction is important in liver hepatocytes which extensively metabolize ingested PCBs and experience varying degreesmore » of oxygen tension during normal physiologic function. This study was designed to assess the effect of hypoxia on AhR transcriptional responses after exposure to 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). Exposure to 1% O{sub 2} prior to PCB 126 treatment significantly inhibited CYP1A1 mRNA and protein expression in human HepG2 and HaCaT cells. CYP1A1 transcriptional activation was significantly decreased upon PCB 126 stimulation under conditions of hypoxia. Additionally, hypoxia pre-treatment reduced PCB 126 induced AhR binding to CYP1 target gene promoters. Importantly, ARNT overexpression rescued cells from the inhibitory effect of hypoxia on XRE-luciferase reporter activity. Therefore, the mechanism of interference of the signaling crosstalk between the AhR and hypoxia pathways appears to be at least in part dependent on ARNT availability. Our results show that AhR activation and CYP1A1 expression induced by PCB 126 were significantly inhibited by hypoxia and hypoxia might therefore play an important role in PCB metabolism and toxicity. - Highlights: • Significant crosstalk exists between AhR and HIF-1α signaling. • Hypoxia perturbs PCB 126 induced AhR

Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harrill, Joshua A.; Hukkanen, Renee R.; Lawson, Marie

2013-10-15

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor which plays a role in the development of multiple tissues and is activated by a large number of ligands, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In order to examine the roles of the AHR in both normal biological development and response to environmental chemicals, an AHR knockout (AHR-KO) rat model was created and compared with an existing AHR-KO mouse. AHR-KO rats harboring either 2-bp or 29-bp deletion mutation in exon 2 of the AHR were created on the Sprague–Dawley genetic background using zinc-finger nuclease (ZFN) technology. Rats harboring either mutation type lacked expressionmore » of AHR protein in the liver. AHR-KO rats were also insensitive to thymic involution, increased hepatic weight and the induction of AHR-responsive genes (Cyp1a1, Cyp1a2, Cyp1b1, Ahrr) following acute exposure to 25 μg/kg TCDD. AHR-KO rats had lower basal expression of transcripts for these genes and also accumulated ∼ 30–45-fold less TCDD in the liver at 7 days post-exposure. In untreated animals, AHR-KO mice, but not AHR-KO rats, had alterations in serum analytes indicative of compromised hepatic function, patent ductus venosus of the liver and persistent hyaloid arteries in the eye. AHR-KO rats, but not AHR-KO mice, displayed pathological alterations to the urinary tract: bilateral renal dilation (hydronephrosis), secondary medullary tubular and uroepithelial degenerative changes and bilateral ureter dilation (hydroureter). The present data indicate that the AHR may play significantly different roles in tissue development and homeostasis and toxicity across rodent species. - Highlights: • An AHR knockout rat was generated on a Sprague–Dawley outbred background. • AHR-KO rats lack expression of AHR protein. • AHR-KO rats are insensitive to TCDD-mediated effects. • Data suggests difference in the role of AHR in tissue development of rats and mice. • Abnormalities in

Assessment of energetic costs of AhR activation by β-naphthoflavone in rainbow trout (Oncorhynchus mykiss) hepatocytes using metabolic flux analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nault, Rance, E-mail: naultran@msu.edu; Abdul-Fattah, Hiba; Mironov, Gleb G.

2013-08-15

Exposure to environmental contaminants such as activators of the aryl hydrocarbon receptor (AhR) leads to the induction of defense and detoxification mechanisms. While these mechanisms allow organisms to metabolize and excrete at least some of these environmental contaminants, it has been proposed that these mechanisms lead to significant energetic challenges. This study tests the hypothesis that activation of the AhR by the model agonist β-naphthoflavone (βNF) results in increased energetic costs in rainbow trout (Oncorhynchus mykiss) hepatocytes. To address this hypothesis, we employed traditional biochemical approaches to examine energy allocation and metabolism including the adenylate energy charge (AEC), protein synthesismore » rates, Na{sup +}/K{sup +}-ATPase activity, and enzyme activities. Moreover, we have used for the first time in a fish cell preparation, metabolic flux analysis (MFA) an in silico approach for the estimation of intracellular metabolic fluxes. Exposure of trout hepatocytes to 1 μM βNF for 48 h did not alter hepatocyte AEC, protein synthesis, or Na{sup +}/K{sup +}-ATPase activity but did lead to sparing of glycogen reserves and changes in activities of alanine aminotransferase and citrate synthase suggesting altered metabolism. Conversely, MFA did not identify altered metabolic fluxes, although we do show that the dynamic metabolism of isolated trout hepatocytes poses a significant challenge for this type of approach which should be considered in future studies. - Highlights: • Energetic costs of AhR activation by βNF was examined in rainbow trout hepatocytes. • Metabolic flux analysis was performed on a fish cell preparation for the first time. • Exposure to βNF led to sparing of glycogen reserves and altered enzyme activities. • Adenylate energy charge was maintained despite temporal changes in metabolism.« less

Lithium-Air Battery: High Performance Cathodes for Lithium-Air Batteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

2010-08-01

BEEST Project: Researchers at Missouri S&T are developing an affordable lithium-air (Li-Air) battery that could enable an EV to travel up to 350 miles on a single charge. Today’s EVs run on Li-Ion batteries, which are expensive and suffer from low energy density compared with gasoline. This new Li-Air battery could perform as well as gasoline and store 3 times more energy than current Li-Ion batteries. A Li-Air battery uses an air cathode to breathe oxygen into the battery from the surrounding air, like a human lung. The oxygen and lithium react in the battery to produce electricity. Current Li-Airmore » batteries are limited by the rate at which they can draw oxygen from the air. The team is designing a battery using hierarchical electrode structures to enhance air breathing and effective catalysts to accelerate electricity production.« less

The citrus flavonone hesperetin attenuates the nuclear translocation of aryl hydrocarbon receptor.

PubMed

Tan, Yan Qin; Chiu-Leung, Leo Clement; Lin, Shu-Mei; Leung, Lai K

2018-08-01

The environmental polycyclic aromatic hydrocarbons (PAH) and dioxins are carcinogens and their adverse effects have been largely attributed to the activation of AhR. Hesperetin is a flavonone found abundantly in citrus fruits and has been shown to be a biologically active agent. In the present study, the effect of hesperetin on the nuclear translocation of AhR and the downstream gene expression was investigated in MCF-7 cells. Confocal microscopy indicated that 7, 12-dimethylbenz[α]anthracene (DMBA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) -induced nuclear translocation of AhR was deterred by hesperetin treatment. The reduced nuclear translocation could also be observed in Western analysis. Reporter-gene assay further illustrated that the induced XRE transactivation was weakened by the treatment of hesperetin. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay demonstrated that the gene expressions of CYP1A1, 1A2, and 1B1 followed the same pattern of AhR translocation. These results suggested that hesperetin counteracted AhR transactivation and suppressed the downstream gene expression. Copyright © 2018 Elsevier Inc. All rights reserved.

Shared epitope-aryl hydrocarbon receptor crosstalk underlies the mechanism of gene-environment interaction in autoimmune arthritis.

PubMed

Fu, Jiaqi; Nogueira, Sarah V; Drongelen, Vincent van; Coit, Patrick; Ling, Song; Rosloniec, Edward F; Sawalha, Amr H; Holoshitz, Joseph

2018-05-01

The susceptibility to autoimmune diseases is affected by genetic and environmental factors. In rheumatoid arthritis (RA), the shared epitope (SE), a five-amino acid sequence motif encoded by RA-associated HLA-DRB1 alleles, is the single most significant genetic risk factor. The risk conferred by the SE is increased in a multiplicative way by exposure to various environmental pollutants, such as cigarette smoke. The mechanism of this synergistic interaction is unknown. It is worth noting that the SE has recently been found to act as a signal transduction ligand that facilitates differentiation of Th17 cells and osteoclasts in vitro and in vivo. Intriguingly, the aryl hydrocarbon receptor (AhR), a transcription factor that mediates the xenobiotic effects of many pollutants, including tobacco combustion products, has been found to activate similar biologic effects. Prompted by these similarities, we sought to determine whether the SE and AhR signaling pathways interact in autoimmune arthritis. Here we uncovered a nuclear factor kappa B-mediated synergistic interaction between the SE and AhR pathways that leads to markedly enhanced osteoclast differentiation and Th17 polarization in vitro. Administration of AhR pathway agonists to transgenic mice carrying human SE-coding alleles resulted in a robust increase in arthritis severity, bone destruction, overabundance of osteoclasts, and IL17-expressing cells in the inflamed joints and draining lymph nodes of arthritic mice. Thus, this study identifies a previously unrecognized mechanism of gene-environment interaction that could provide insights into the well-described but poorly understood amplification of the genetic risk for RA upon exposure to environmental pollutants. Copyright © 2018 the Author(s). Published by PNAS.

High-Energy-Density Metal-Oxygen Batteries: Lithium-Oxygen Batteries vs Sodium-Oxygen Batteries.

PubMed

Song, Kyeongse; Agyeman, Daniel Adjei; Park, Mihui; Yang, Junghoon; Kang, Yong-Mook

2017-12-01

The development of next-generation energy-storage devices with high power, high energy density, and safety is critical for the success of large-scale energy-storage systems (ESSs), such as electric vehicles. Rechargeable sodium-oxygen (Na-O 2 ) batteries offer a new and promising opportunity for low-cost, high-energy-density, and relatively efficient electrochemical systems. Although the specific energy density of the Na-O 2 battery is lower than that of the lithium-oxygen (Li-O 2 ) battery, the abundance and low cost of sodium resources offer major advantages for its practical application in the near future. However, little has so far been reported regarding the cell chemistry, to explain the rate-limiting parameters and the corresponding low round-trip efficiency and cycle degradation. Consequently, an elucidation of the reaction mechanism is needed for both lithium-oxygen and sodium-oxygen cells. An in-depth understanding of the differences and similarities between Li-O 2 and Na-O 2 battery systems, in terms of thermodynamics and a structural viewpoint, will be meaningful to promote the development of advanced metal-oxygen batteries. State-of-the-art battery design principles for high-energy-density lithium-oxygen and sodium-oxygen batteries are thus reviewed in depth here. Major drawbacks, reaction mechanisms, and recent strategies to improve performance are also summarized. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Lithium Ion Batteries

NASA Technical Reports Server (NTRS)

1997-01-01

Lithium ion batteries, which use a new battery chemistry, are being developed under cooperative agreements between Lockheed Martin, Ultralife Battery, and the NASA Lewis Research Center. The unit cells are made in flat (prismatic) shapes that can be connected in series and parallel to achieve desired voltages and capacities. These batteries will soon be marketed to commercial original-equipment manufacturers and thereafter will be available for military and space use. Current NiCd batteries offer about 35 W-hr/kg compared with 110 W-hr/kg for current lithium ion batteries. Our ultimate target for these batteries is 200 W-hr/kg.

Battery Safety Basics

ERIC Educational Resources Information Center

Roy, Ken

2010-01-01

Batteries commonly used in flashlights and other household devices produce hydrogen gas as a product of zinc electrode corrosion. The amount of gas produced is affected by the batteries' design and charge rate. Dangerous levels of hydrogen gas can be released if battery types are mixed, batteries are damaged, batteries are of different ages, or…

Identification of benzothiazole derivatives and polycyclic aromatic hydrocarbons as aryl hydrocarbon receptor agonists present in tire extracts.

PubMed

He, Guochun; Zhao, Bin; Denison, Michael S

2011-08-01

Leachate from rubber tire material contains a complex mixture of chemicals previously shown to produce toxic and biological effects in aquatic organisms. The ability of these leachates to induce Ah receptor (AhR)-dependent cytochrome P4501A1 expression in fish indicated the presence of AhR active chemicals, but the responsible chemicals and their direct interaction with the AhR signaling pathway were not examined. Using a combination of AhR-based bioassays, we have demonstrated the ability of tire extract to stimulate both AhR DNA binding and AhR-dependent gene expression and confirmed that the responsible chemicals were metabolically labile. The application of CALUX (chemical-activated luciferase gene expression) cell bioassay-driven toxicant identification evaluation not only revealed that tire extract contained a variety of known AhR-active polycyclic aromatic hydrocarbons but also identified 2-methylthiobenzothiazole and 2-mercaptobenzothiazole as AhR agonists. Analysis of a structurally diverse series of benzothiazoles identified many that could directly stimulate AhR DNA binding and transiently activate the AhR signaling pathway and identified benzothiazoles as a new class of AhR agonists. In addition to these compounds, the relatively high AhR agonist activity of a large number of fractions strongly suggests that tire extract contains a large number of physiochemically diverse AhR agonists whose identities and toxicological/biological significances are unknown. Copyright © 2011 SETAC.

Effect of KOH concentration on LEO cycle life of IPV nickel-hydrogen flight battery cells

NASA Technical Reports Server (NTRS)

Smithrick, John J.; Hall, Stephen W.

1990-01-01

A breakthrough in low earth orbit (LEO) cycle life of individual pressure vessel (IPV) nickel hydrogen battery cells was reported. The cycle life of boiler plate cells containing 26 percent potassium hydroxide (KOH) electrolyte was about 40,000 LEO cycles compared to 3500 cycles for cells containing 31 percent KOH. The effect of KOH concentration on cycle life was studied. The cycle regime was a stressful accelerated LEO, which consisted of a 27.5 min charge followed by a 17.5 min charge (2 x normal rate). The depth of discharge (DOD) was 80 percent. The cell temperature was maintained at 23 C. The next step is to validate these results using flight hardware and a real time LEO test. NASA Lewis has a contract with the Naval Weapons Support Center (NWSC), Crane, Indiana, to validate the boiler plate test results. Six 48 A-hr Hughes recirculation design IPV nickel-hydrogen flight battery cells are being evaluated. Three of the cells contain 26 percent KOH (test cells) and three contain 31 percent KOH (control cells). They are undergoing real time LEO cycle life testing. The cycle regime is a 90-min LEO orbit consisting of a 54-min charge followed by a 36-min discharge. The depth-of-discharge is 80 percent. The cell temperature is maintained at 10 C. The cells were cycled for over 8000 cycles in the continuing test. There were no failures for the cells containing 26 percent KOH. There was two failures, however, for the cells containing 31 percent KOH.

Effect of KOH concentration on LEO cycle life of IPV nickel-hydrogen flight battery cells

NASA Technical Reports Server (NTRS)

Smithrick, John J.; Hall, Stephen W.

1990-01-01

A breakthrough in the low-earth-orbit (LEO) cycle life of individual pressure vessel (IPV) nickel hydrogen battery cells is reported. The cycle life of boiler plate cells containing 26 percent potassium hydroxide (KOH) electrolyte was about 40,000 LEO cycles compared to 3500 cycles for cells containing 31 percent KOH. The effect of KOH concentration on cycle life was studied. The cycle regime was a stressful accelerated LEO, which consisted of a 27.5 min charge followed by a 17.5 min charge (2 x normal rate). The depth of discharge (DOD) was 80 percent. The cell temperature was maintained at 23 C. The next step is to validate these results using flight hardware and real time LEO test. NASA Lewis has a contract with the Naval Weapons Support Center (NWSC), Crane, Indiana to validate the boiler plate test results. Six 48 A-hr Hughes recirculation design IPV nickel-hydrogen flight battery cells are being evaluated. Three of the cells contain 26 percent KOH (test cells) and three contain 31 percent KOH (control cells). They are undergoing real time LEO cycle life testing. The cycle regime is a 90-min LEO orbit consisting of a 54-min charge followed by a 36-min discharge. The depth-of-discharge is 80 percent. The cell temperature is maintained at 10 C. The cells were cycled for over 8000 cycles in the continuing test. There were no failures for the cells containing 26 percent KOH. There were two failures, however, for the cells containing 31 percent KOH.

Indole-3-carbinol induces G1 cell cycle arrest and apoptosis through aryl hydrocarbon receptor in THP-1 monocytic cell line.

PubMed

Mohammadi, Saeed; Seyedhosseini, Fakhri Sadat; Behnampour, Nasser; Yazdani, Yaghoub

2017-10-01

The role of aryl hydrocarbon receptor (AhR) in carcinogenesis has been studied recently. Indole-3-carbinol (I3C) is an AhR agonist and a potential anticancer agent. Here, we investigated the effects of I3C on cell cycle progression and apoptosis through activation of AhR on THP-1 acute myeloid leukemia (AML) cell line. MTT viability assay was used to measure the cytotoxic effects of I3C on THP-1 cells. Apoptosis and cell cycle assays were investigated using flow cytometry. Real time RT-PCR was conducted to measure the alterations in the expression of AhR gene, key genes associated with AhR activation (IL1β and CYP1A1) and major genes involved in cell cycle regulation and apoptosis including P27, P21, CDK2, P53, BCL2 and FasR. Our findings revealed that I3C inhibits the proliferation of THP-1 cells in a dose- and time-dependent manner with minimal toxicity over normal monocytes. The AhR target genes (CYP1A1, IL1β) were overexpressed upon I3C treatment (p < .05 to p < .001). The antiproliferative effects of I3C were in association with programed cell death. I3C downregulated BCL2 and upregulated FasR in THP-1 cells (p < .05 to p < .001). G1 cell cycle arrest was also observed using flow cytometry. G1-acting cell cycle genes (P21, P27 and P53) were overexpressed (p < .05 to p < .001), while CDK2 was downregulated upon I3C treatment (p < .01 to p < .001). I3C could exert its antileukemic effects through AhR activation which is associated with programed cell death and G1 cell cycle arrest in a dose- and time-dependent manner. Therefore, AhR could be targeted as a novel treatment possibility in AML.

6-shogaol, a major compound in ginger, induces aryl hydrocarbon receptor-mediated transcriptional activity and gene expression.

PubMed

Yoshida, Kazutaka; Satsu, Hideo; Mikubo, Ayano; Ogiwara, Haru; Yakabe, Takafumi; Inakuma, Takahiro; Shimizu, Makoto

2014-06-18

Xenobiotics are usually detoxified by drug-metabolizing enzymes and excreted from the body. The expression of many of drug-metabolizing enzymes is regulated by the aryl hydrocarbon receptor (AHR). Some substances in vegetables have the potential to be AHR ligands. To search for vegetable components that exhibit AHR-mediated transcriptional activity, we assessed the activity of vegetable extracts and identified the active compounds using the previously established stable AHR-responsive HepG2 cell line. Among the hot water extracts of vegetables, the highest activity was found in ginger. The ethyl acetate fraction of the ginger hot water extract remarkably induced AHR-mediated transcriptional activity, and the major active compound was found to be 6-shogaol. Subsequently, the mRNA levels of AHR-targeting drug-metabolizing enzymes (CYP1A1, UGT1A1, and ABCG 2) and the protein level of CYP1A1 in HepG2 cells were shown to be increased by 6-shogaol. This is the first report that 6-shogaol can regulate the expression of detoxification enzymes by AHR activation.

AhR ligands, malassezin, and indolo[3,2-b]carbazole are selectively produced by Malassezia furfur strains isolated from seborrheic dermatitis.

PubMed

Gaitanis, George; Magiatis, Prokopios; Stathopoulou, Konstantina; Bassukas, Ioannis D; Alexopoulos, Evangelos C; Velegraki, Aristea; Skaltsounis, Alexios-Leandros

2008-07-01

Malassezia yeasts are connected with seborrheic dermatitis (SD) whereas M. furfur pathogenicity is associated with the production of bioactive indoles. In this study, the production of indoles by M. furfur isolates from healthy and diseased skin was compared, the respective HPLC patterns were analyzed, and substances that are preferentially synthesized by strains isolated from SD lesions were isolated and characterized. Malassezin, pityriacitrin, indole-3-carbaldehyde, and indolo[3,2-b]carbazole (ICZ) were isolated by HPLC from extracts of M. furfur grown in L-tryptophan agar, and identified by nuclear magnetic resonance and mass spectroscopy. Of these, ICZ, a potent ligand of the aryl hydrocarbon receptor (AhR), is described for the first time to our knowledge as a M. furfur metabolite. HPLC-photodiode array detection analysis of strain extracts from 7 healthy subjects and 10 SD patients showed that M. furfur isolates from only SD patients consistently produce malassezin and ICZ. This discriminatory production of AhR agonists provides initial evidence for a previously unreported mechanism triggering development of SD and indicates that the variable pathogenicity patterns recorded for M. furfur-associated SD conditions may be attributed to selective production (P<0.001) of measurable bioactive indoles.

Battery Thermal Characterization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keyser, Matthew A

The operating temperature is critical in achieving the right balance between performance, cost, and life for both Li-ion batteries and ultracapacitors. The chemistries of advanced energy-storage devices - such as lithium-based batteries - are very sensitive to operating temperature. High temperatures degrade batteries faster while low temperatures decrease their power and capacity, affecting vehicle range, performance, and cost. Understanding heat generation in battery systems - from the individual cells within a module, to the inter-connects between the cells, and across the entire battery system - is imperative for designing effective thermal-management systems and battery packs. At NREL, we have developedmore » unique capabilities to measure the thermal properties of cells and evaluate thermal performance of battery packs (air or liquid cooled). We also use our electro-thermal finite element models to analyze the thermal performance of battery systems in order to aid battery developers with improved thermal designs. NREL's tools are used to meet the weight, life, cost, and volume goals set by the U.S. Department of Energy for electric drive vehicles.« less

Association between individual and combined SNPs in genes related to innate immunity and incidence of CMV infection in seropositive kidney transplant recipients.

PubMed

Fernández-Ruiz, M; Corrales, I; Arias, M; Campistol, J M; Giménez, E; Crespo, J; López-Oliva, M O; Beneyto, I; Martín-Moreno, P L; Llamas-Fuente, F; Gutiérrez, A; García-Álvarez, T; Guerra-Rodríguez, R; Calvo, N; Fernández-Rodríguez, A; Tabernero-Romo, J M; Navarro, M D; Ramos-Verde, A; Aguado, J M; Navarro, D

2015-05-01

In this study, we assessed the association between single-nucleotide polymorphisms (SNPs) in seven candidate genes involved in orchestrating the immune response against cytomegalovirus (CMV) and the 12-month incidence of CMV infection in 315 CMV-seropositive kidney transplant (KT) recipients. Patients were managed either by antiviral prophylaxis or preemptive therapy. CMV infection occurred in 140 patients (44.4%), including 13 episodes of disease. After adjusting for various clinical covariates, patients harboring T-allele genotypes of interleukin-28B (IL28B) (rs12979860) SNP had lower incidence of CMV infection (adjusted hazard ratio [aHR]: 0.66; 95% confidence interval [CI]: 0.46-0.96; p-value = 0.029). In the analysis restricted to patients not receiving prophylaxis, carriers of the TT genotype of toll-like receptor 9 (TLR9) (rs5743836) SNP had lower incidence of infection (aHR: 0.61; 95% CI: 0.38-0.96; p-value = 0.035), whereas the GG genotype of dendritic cell-specific ICAM 3-grabbing nonintegrin (DC-SIGN) (rs735240) SNP exerted the opposite effect (aHR: 1.86; 95% CI: 1.18-2.94; p-value = 0.008). An independent association was found between the number of unfavorable SNP genotypes carried by the patient and the incidence of CMV infection. In conclusion, specific SNPs in IL28B, TLR9 and DC-SIGN genes may play a role in modulating the susceptibility to CMV infection in CMV-seropositive KT recipients. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Dioxin activation of CYP1A5 promoter/enhancer regions from two avian species, common cormorant (Phalacrocorax carbo) and chicken (Gallus gallus): Association with aryl hydrocarbon receptor 1 and 2 isoforms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Jin-Seon; Kim, Eun-Young; Iwata, Hisato

The present study focuses on the molecular mechanism and interspecies differences in susceptibility of avian aryl hydrocarbon receptor (AHR)-cytochrome P4501A (CYP1A) signaling pathway. By the cloning of 5'-flanking regions of CYP1A5 gene from common cormorant (Phalacrocorax carbo) and chicken (Gallus gallus), seven putative xenobiotic response elements (XREs) were identified within 2.7 kb upstream region of common cormorant CYP1A5 (ccCYP1A5), and six XREs were found within 0.9 kb of chicken CYP1A5 (ckCYP1A5). Analysis of sequential deletion and mutagenesis of the binding sites in avian CYP1A5 genes by in vitro reporter gene assays revealed that two XREs at -613 bp and -1585more » bp in ccCYP1A5, and one XRE at -262 bp in ckCYP1A5 conferred TCDD-responsiveness. The binding of AHR1 with AHR nuclear translocator 1 (ARNT1) to the functional XRE in a TCDD-dependent manner was verified with gel shift assays, suggesting that avian CYP1A5 is induced by TCDD through AHR1/ARNT1 signaling pathway as well as mammalian CYP1A1 but through a distinct pathway from mammalian CYP1A2, an ortholog of the CYP1A5. TCDD-EC{sub 50} for the transcriptional activity in both cormorant AHR1- and AHR2-ccCYP1A5 reporter construct was 10-fold higher than that in chicken AHR1-ckCYP1A5 reporter construct. In contrast, chicken AHR2 showed no TCDD-dependent response. The TCDD-EC{sub 50} for CYP1A5 transactivation was altered by switching AHR1 between the two avian species, irrespective of the species from which the regulatory region of CYP1A5 gene originates. Therefore, the structural difference in AHR, not the CYP1A5 regulatory region may be a major factor to account for the dioxin susceptibility in avian species.« less

Microbiome-Derived Tryptophan Metabolites and Their Aryl Hydrocarbon Receptor-Dependent Agonist and Antagonist Activities

PubMed Central

Jin, Un-Ho; Lee, Syng-Ook; Sridharan, Gautham; Lee, Kyongbum; Davidson, Laurie A.; Jayaraman, Arul; Chapkin, Robert S.; Alaniz, Robert

2014-01-01

The tryptophan metabolites indole, indole-3-acetate, and tryptamine were identified in mouse cecal extracts and fecal pellets by mass spectrometry. The aryl hydrocarbon receptor (AHR) agonist and antagonist activities of these microbiota-derived compounds were investigated in CaCo-2 intestinal cells as a model for understanding their interactions with colonic tissue, which is highly aryl hydrocarbon (Ah)–responsive. Activation of Ah-responsive genes demonstrated that tryptamine and indole 3-acetate were AHR agonists, whereas indole was an AHR antagonist that inhibited TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)–induced CYP1A1 expression. In contrast, the tryptophan metabolites exhibited minimal anti-inflammatory activities, whereas TCDD decreased phorbol ester-induced CXCR4 [chemokine (C-X-C motif) receptor 4] gene expression, and this response was AHR dependent. These results demonstrate that the tryptophan metabolites indole, tryptamine, and indole-3-acetate modulate AHR-mediated responses in CaCo-2 cells, and concentrations of indole that exhibit AHR antagonist activity (100–250 μM) are detected in the intestinal microbiome. PMID:24563545

Sequence variants at CYP1A1–CYP1A2 and AHR associate with coffee consumption

PubMed Central

Sulem, Patrick; Gudbjartsson, Daniel F.; Geller, Frank; Prokopenko, Inga; Feenstra, Bjarke; Aben, Katja K.H.; Franke, Barbara; den Heijer, Martin; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Yanek, Lisa R.; Becker, Lewis C.; Boyd, Heather A.; Stacey, Simon N.; Walters, G. Bragi; Jonasdottir, Adalbjorg; Thorleifsson, Gudmar; Holm, Hilma; Gudjonsson, Sigurjon A.; Rafnar, Thorunn; Björnsdottir, Gyda; Becker, Diane M.; Melbye, Mads; Kong, Augustine; Tönjes, Anke; Thorgeirsson, Thorgeir; Thorsteinsdottir, Unnur; Kiemeney, Lambertus A.; Stefansson, Kari

2011-01-01

Coffee is the most commonly used stimulant and caffeine is its main psychoactive ingredient. The heritability of coffee consumption has been estimated at around 50%. We performed a meta-analysis of four genome-wide association studies of coffee consumption among coffee drinkers from Iceland (n = 2680), the Netherlands (n = 2791), the Sorbs Slavonic population isolate in Germany (n = 771) and the USA (n = 369) using both directly genotyped and imputed single nucleotide polymorphisms (SNPs) (2.5 million SNPs). SNPs at the two most significant loci were also genotyped in a sample set from Iceland (n = 2430) and a Danish sample set consisting of pregnant women (n = 1620). Combining all data, two sequence variants significantly associated with increased coffee consumption: rs2472297-T located between CYP1A1 and CYP1A2 at 15q24 (P = 5.4 · 10−14) and rs6968865-T near aryl hydrocarbon receptor (AHR) at 7p21 (P = 2.3 · 10−11). An effect of ∼0.2 cups a day per allele was observed for both SNPs. CYP1A2 is the main caffeine metabolizing enzyme and is also involved in drug metabolism. AHR detects xenobiotics, such as polycyclic aryl hydrocarbons found in roasted coffee, and induces transcription of CYP1A1 and CYP1A2. The association of these SNPs with coffee consumption was present in both smokers and non-smokers. PMID:21357676

Potassium Secondary Batteries.

PubMed

Eftekhari, Ali; Jian, Zelang; Ji, Xiulei

2017-02-08

Potassium may exhibit advantages over lithium or sodium as a charge carrier in rechargeable batteries. Analogues of Prussian blue can provide millions of cyclic voltammetric cycles in aqueous electrolyte. Potassium intercalation chemistry has recently been demonstrated compatible with both graphite and nongraphitic carbons. In addition to potassium-ion batteries, potassium-O 2 (or -air) and potassium-sulfur batteries are emerging. Additionally, aqueous potassium-ion batteries also exhibit high reversibility and long cycling life. Because of potentially low cost, availability of basic materials, and intriguing electrochemical behaviors, this new class of secondary batteries is attracting much attention. This mini-review summarizes the current status, opportunities, and future challenges of potassium secondary batteries.

VRLA automotive batteries for stop&go and dual battery systems

NASA Astrophysics Data System (ADS)

May, G. J.; Calasanzio, D.; Aliberti, R.

The electrical power requirements for vehicles are continuing to increase and evolve. A substantial amount of effort has been directed towards the development of 36/42 V systems as a route to higher power with reduced current levels but high implementation costs have resulted in the introduction of these systems becoming deferred. In the interim, however, alternator power outputs at 14 V are being increased substantially and at the same time the requirements for batteries are becoming more intensive. In particular, stop&go systems and wire-based vehicle systems are resulting in new demands. For stop&go, the engine is stopped each time the vehicle comes to rest and is restarted when the accelerator is pressed again. This results in an onerous duty cycle with many shallow discharge cycles. Flooded lead-acid batteries cannot meet this duty cycle and valve-regulated lead-acid (VRLA) batteries are needed to meet the demands that are applied. For wire-based systems, such as brake-by-wire or steer-by-wire, electrical power has become more critical and although the alternator and battery provide double redundancy, triple redundancy with a small reserve battery is specified. In this case, a small VRLA battery can be used and is optimised for standby service rather than for repeated discharges. The background to these applications is considered and test results under simulated operating conditions are discussed. Good performance can be obtained in batteries adapted for both applications. Battery management is also critical for both applications: in stop&go service, the state-of-charge (SOC) and state-of-health (SOH) need to be monitored to ensure that the vehicle can be restarted; for reserve or back-up batteries, the SOC and SOH are monitored to verify that the battery is always capable of carrying out the duty cycle if required. Practical methods of battery condition monitoring will be described.

Identification of Benzothiazole Derivatives and Polycyclic Aromatic Hydrocarbons as Aryl Hydrocarbon Receptor Agonists Present in Tire Extracts

PubMed Central

He, Guochun; Zhao, Bin; Denison, Michael S.

2012-01-01

Leachate from rubber tire material contains a complex mixture of chemicals previously shown to produce toxic and biological effects in aquatic organisms. While the ability of these leachates to induce Ah receptor (AhR)-dependent cytochrome P4501A1 expression in fish indicated the presence of AhR active chemicals, the responsible chemical(s) and their direct interaction with the AhR signaling pathway were not examined. Using a combination of AhR-based bioassays, we have demonstrated the ability of tire extract to stimulate both AhR DNA binding and AhR-dependent gene expression and confirmed that the responsible chemical(s) was metabolically labile. The application of CALUX (Chemical-Activated LUciferase gene eXpression) cell bioassay-driven toxicant identification evaluation not only revealed that tire extract contained a variety of known AhR-active polycyclic aromatic hydrocarbons, but also identified 2-methylthiobenzothiazole and 2-mercaptobenzothiazole as AhR agonists. Analysis of a structurally diverse series of benzothiazoles identified many that could directly stimulate AhR DNA binding and transiently activate the AhR signaling pathway and identified benzothiazoles as a new class of AhR agonists. In addition to these compounds, the relatively high AhR agonist activity of a large number of fractions strongly suggests that tire extract contains a large number of physiochemically diverse AhR agonists whose identities and toxicological/biological significances are unknown. PMID:21590714

Metabolomics Reveals Aryl Hydrocarbon Receptor Activation Induces Liver and Mammary Gland Metabolic Dysfunction in Lactating Mice.

PubMed

Belton, Kerry R; Tian, Yuan; Zhang, Limin; Anitha, Mallappa; Smith, Philip B; Perdew, Gary H; Patterson, Andrew D

2018-04-06

The liver and the mammary gland have complementary metabolic roles during lactation. Substrates synthesized by the liver are released into the circulation and are taken up by the mammary gland for milk production. The aryl hydrocarbon receptor (AHR) has been identified as a lactation regulator in mice, and its activation has been associated with myriad morphological, molecular, and functional defects such as stunted gland development, decreased milk production, and changes in gene expression. In this study, we identified adverse metabolic changes in the lactation network (mammary, liver, and serum) associated with AHR activation using 1 H nuclear magnetic resonance (NMR)-based metabolomics. Pregnant mice expressing Ahr d (low affinity) or Ahr b (high affinity) were fed diets containing beta naphthoflavone (BNF), a potent AHR agonist. Mammary, serum, and liver metabolomics analysis identified significant changes in lipid and TCA cycle intermediates in the Ahr b mice. We observed decreased amino acid and glucose levels in the mammary gland extracts of Ahr b mice fed BNF. The serum of BNF fed Ahr b mice had significant changes in LDL/VLDL (increased) and HDL, PC, and GPC (decreased). Quantitative PCR analysis revealed ∼50% reduction in the expression of key lactogenesis mammary genes including whey acid protein, α-lactalbumin, and β-casein. We also observed morphologic and developmental disruptions in the mammary gland that are consistent with previous reports. Our observations support that AHR activity contributes to metabolism regulation in the lactation network.

Polyvinyl alcohol battery separator containing inert filler. [alkaline batteries

NASA Technical Reports Server (NTRS)

Sheibley, D. W.; Hsu, L. C.; Manzo, M. A. (Inventor)

1981-01-01

A cross-linked polyvinyl alcohol battery separator is disclosed. A particulate filler, inert to alkaline electrolyte of an alkaline battery, is incorporated in the separator in an amount of 1-20% by weight, based on the weight of the polyvinyl alcohol, and is dispersed throughout the product. Incorporation of the filler enhances performance and increases cycle life of alkaline batteries when compared with batteries containing a similar separator not containing filler. Suitable fillers include titanates, silicates, zirconates, aluminates, wood floor, lignin, and titania. Particle size is not greater than about 50 microns.

Depressive-like effect of prenatal exposure to DDT involves global DNA hypomethylation and impairment of GPER1/ESR1 protein levels but not ESR2 and AHR/ARNT signaling.

PubMed

Kajta, Malgorzata; Wnuk, Agnieszka; Rzemieniec, Joanna; Litwa, Ewa; Lason, Wladyslaw; Zelek-Molik, Agnieszka; Nalepa, Irena; Rogóż, Zofia; Grochowalski, Adam; Wojtowicz, Anna K

2017-07-01

Several lines of evidence suggest that exposures to Endocrine Disrupting Chemicals (EDCs) such as pesticides increase the risks of neuropsychiatric disorders. Despite extended residual persistence of dichlorodiphenyltrichloroethane (DDT) in the environment, the mechanisms of perinatal actions of DDT that could account for adult-onset of depression are largely unknown. This study demonstrated the isomer-specific induction of depressive-like behavior and impairment of Htr1a/serotonin signaling in one-month-old mice that were prenatally exposed to DDT. The effects were reversed by the antidepressant citalopram as evidenced in the forced swimming (FST) and tail suspension (TST) tests in the male and female mice. Prenatally administered DDT accumulated in mouse brain as determined with gas chromatography and tandem mass spectrometry, led to global DNA hypomethylation, and altered the levels of methylated DNA in specific genes. The induction of depressive-like behavior and impairment of Htr1a/serotonin signaling were accompanied by p,p'-DDT-specific decrease in the levels of estrogen receptors i.e. ESR1 and/or GPER1 depending on sex. In contrast, o,p'-DDT did not induce depressive-like effects and exhibited quite distinct pattern of biochemical alterations that was related to aryl hydrocarbon receptor (AHR), its nuclear translocator ARNT, and ESR2. Exposure to o,p'-DDT increased AHR expression in male and female brains, and reduced expression levels of ARNT and ESR2 in the female brains. The evolution of p,p'-DDT-induced depressive-like behavior was preceded by attenuation of Htr1a and Gper1/GPER1 expression as observed in the 7-day-old mouse pups. Because p,p'-DDT caused sex- and age-independent attenuation of GPER1, we suggest that impairment of GPER1 signaling plays a key role in the propagation of DDT-induced depressive-like symptoms. Copyright © 2017 Elsevier Ltd. All rights reserved.

New insights to the role of aryl hydrocarbon receptor in bone phenotype and in dioxin-induced modulation of bone microarchitecture and material properties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herlin, Maria, E-mail: maria.herlin@ki.se; Finnilä, Mikko A.J., E-mail: mikko.finnila@oulu.fi; Department of Anatomy and Cell Biology, Institute of Biomedicine, University of Oulu, Oulu

Bone is a target for high affinity aryl hydrocarbon receptor (AHR) ligands, such as dioxins. Although bone morphology, mineral density and strength are sensitive endpoints of dioxin toxicity, less is known about effects on bone microarchitecture and material properties. This study characterizes TCDD-induced modulations of bone tissue, and the role of AHR in dioxin-induced bone toxicity and for normal bone phenotype. Six AHR-knockout (Ahr{sup −/−}) and wild-type (Ahr{sup +/+}) mice of both genders were exposed to TCDD weekly for 10 weeks, at a total dose of 200 μg/kg bw. Bones were examined with micro-computed tomography, nanoindentation and biomechanical testing. Serummore » levels of bone remodeling markers were analyzed, and the expression of genes related to osteogenic differentiation was profiled using PCR array. In Ahr{sup +/+} mice, TCDD-exposure resulted in harder bone matrix, thinner and more porous cortical bone, and a more compact trabecular bone compartment. Bone remodeling markers and altered expression of a number of osteogenesis related genes indicated imbalanced bone remodeling. Untreated Ahr{sup −/−} mice displayed a slightly modified bone phenotype as compared with untreated Ahr{sup +/+} mice, while TCDD exposure caused only a few changes in bones of Ahr{sup −/−} mice. Part of the effects of both TCDD-exposure and AHR-deficiency were gender dependent. In conclusion, exposure of adult mice to TCDD resulted in harder bone matrix, thinner cortical bone, mechanically weaker bones and most notably, increased trabecular bone volume fraction in Ahr{sup +/+} mice. AHR is involved in bone development of a normal bone phenotype, and is crucial for manifestation of TCDD-induced bone alterations. - Highlights: • TCDD disrupts bone remodeling resulting in altered cortical and trabecular bone. • In trabecular bone an anabolic effect is observed. • Cortical bone is thinner, more porous, harder, stiffer and mechanically weaker. • AHR

A splicing mutation in Aryl Hydrocarbon Receptor associated with retinitis pigmentosa.

PubMed

Zhou, Yu; Li, Shijin; Huang, Lulin; Yang, Yeming; Zhang, Lin; Yang, Mu; Liu, Wenjing; Ramasamy, Kim; Jiang, Zhilin; Sundaresan, Periasamy; Zhu, Xianjun; Yang, Zhenglin

2018-05-02

Retinitis pigmentosa (RP) refers to a group of retinal degenerative diseases, which often lead to vision loss. Although 70 genes have been identified in RP patients, the genetic cause of approximately 30% of RP cases remains unknown. We aimed to identify the cause of the disease in a cohort of RP families by whole exome sequencing. A rare homozygous splicing variant, c.1160 + 1G>A, which introduced skipping of exon 9 of the aryl hydrocarbon receptor (AHR), was identified in family RD-134. This variant is very rare in several exome databases and leads to skipping of exon 9 in the transcript. AHR is expressed in the human retina and is a ligand-activated transcription factor with multiple functions. Mutant AHR failed to promote 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced Xenobiotic Responsive Element (XRE) luciferase activity. In parallel, mutation in AHR abolished activation of its downstream target gene, such as CYP1A1 and CYP1A2. To investigate the in vivo roles of Ahr in the retina, we generated a retina-specific conditional knockout mouse model of Ahr. Comparing with wildtype mouse, Ahr knockout mice exhibited reduced electroretinogram responses at 9 months of age. Retinal histology revealed Retinal histology showed the degeneration of photoreceptors with a thinner outer nuclear layer. Thus, our data demonstrate that AHR is associated with RP.

Interaction of Diuron and Related Substituted Phenylureas with the Ah Receptor Pathway

PubMed Central

Zhao, Bin; Baston, David S.; Hammock, Bruce; Denison, Michael S.

2011-01-01

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates many of the biological and toxicological actions of structurally diverse chemicals, including the ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin. Here, we have examined the ability of diuron, a widely used herbicide, and several structurally related substituted phenylureas to bind to and activate/inhibit the AhR and AhR signal transduction. Diuron induced CYP1A1 mRNA levels in mouse hepatoma (Hepa1c1c7) cells and AhR-dependent luciferase reporter gene expression in stably transfected mouse, rat, guinea pig, and human cell lines. In addition, ligand binding and gel retardation analysis demonstrated the ability of diuron to competitively bind to and stimulate AhR transformation and DNA binding in vitro and in intact cells. Several structurally related substituted phenylureas competitively bound to the guinea pig hepatic cytosolic AhR, inhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced AhR-dependent luciferase reporter gene expression in a species-specific manner and stimulated AhR transformation and DNA binding, consistent with their role as partial AhR agonists. These results demonstrate not only that diuron and related substituted phenylureas are AhR ligands but also that exposure to these chemicals could induce/inhibit AhR-dependent biological effects. PMID:16788953

Alkaline battery operational methodology

DOEpatents

Sholklapper, Tal; Gallaway, Joshua; Steingart, Daniel; Ingale, Nilesh; Nyce, Michael

2016-08-16

Methods of using specific operational charge and discharge parameters to extend the life of alkaline batteries are disclosed. The methods can be used with any commercial primary or secondary alkaline battery, as well as with newer alkaline battery designs, including batteries with flowing electrolyte. The methods include cycling batteries within a narrow operating voltage window, with minimum and maximum cut-off voltages that are set based on battery characteristics and environmental conditions. The narrow voltage window decreases available capacity but allows the batteries to be cycled for hundreds or thousands of times.

Blood cell gene expression associated with cellular stress defense is modulated by antioxidant-rich food in a randomised controlled clinical trial of male smokers.

PubMed

Bøhn, Siv K; Myhrstad, Mari C; Thoresen, Magne; Holden, Marit; Karlsen, Anette; Tunheim, Siv Haugen; Erlund, Iris; Svendsen, Mette; Seljeflot, Ingebjørg; Moskaug, Jan O; Duttaroy, Asim K; Laake, Petter; Arnesen, Harald; Tonstad, Serena; Collins, Andrew; Drevon, Christan A; Blomhoff, Rune

2010-09-16

Plant-based diets rich in fruit and vegetables can prevent development of several chronic age-related diseases. However, the mechanisms behind this protective effect are not elucidated. We have tested the hypothesis that intake of antioxidant-rich foods can affect groups of genes associated with cellular stress defence in human blood cells. NCT00520819 http://clinicaltrials.gov. In an 8-week dietary intervention study, 102 healthy male smokers were randomised to either a diet rich in various antioxidant-rich foods, a kiwifruit diet (three kiwifruits/d added to the regular diet) or a control group. Blood cell gene expression profiles were obtained from 10 randomly selected individuals of each group. Diet-induced changes on gene expression were compared to controls using a novel application of the gene set enrichment analysis (GSEA) on transcription profiles obtained using Affymetrix HG-U133-Plus 2.0 whole genome arrays. Changes were observed in the blood cell gene expression profiles in both intervention groups when compared to the control group. Groups of genes involved in regulation of cellular stress defence, such as DNA repair, apoptosis and hypoxia, were significantly upregulated (GSEA, FDR q-values < 5%) by both diets compared to the control group. Genes with common regulatory motifs for aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (AhR/ARNT) were upregulated by both interventions (FDR q-values < 5%). Plasma antioxidant biomarkers (polyphenols/carotenoids) increased in both groups. The observed changes in the blood cell gene expression profiles suggest that the beneficial effects of a plant-based diet on human health may be mediated through optimization of defence processes.

Dry cell battery poisoning

MedlinePlus

Batteries - dry cell ... Acidic dry cell batteries contain: Manganese dioxide Ammonium chloride Alkaline dry cell batteries contain: Sodium hydroxide Potassium hydroxide Lithium dioxide dry cell batteries ...

Batteries for Electric Vehicles

NASA Technical Reports Server (NTRS)

Conover, R. A.

1985-01-01

Report summarizes results of test on "near-term" electrochemical batteries - (batteries approaching commercial production). Nickel/iron, nickel/zinc, and advanced lead/acid batteries included in tests and compared with conventional lead/acid batteries. Batteries operated in electric vehicles at constant speed and repetitive schedule of accerlerating, coasting, and braking.

Battery control system for hybrid vehicle and method for controlling a hybrid vehicle battery

DOEpatents

Bockelmann, Thomas R [Battle Creek, MI; Hope, Mark E [Marshall, MI; Zou, Zhanjiang [Battle Creek, MI; Kang, Xiaosong [Battle Creek, MI

2009-02-10

A battery control system for hybrid vehicle includes a hybrid powertrain battery, a vehicle accessory battery, and a prime mover driven generator adapted to charge the vehicle accessory battery. A detecting arrangement is configured to monitor the vehicle accessory battery's state of charge. A controller is configured to activate the prime mover to drive the generator and recharge the vehicle accessory battery in response to the vehicle accessory battery's state of charge falling below a first predetermined level, or transfer electrical power from the hybrid powertrain battery to the vehicle accessory battery in response to the vehicle accessory battery's state of charge falling below a second predetermined level. The invention further includes a method for controlling a hybrid vehicle powertrain system.

1992 five year battery forecast

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amistadi, D.

1992-12-01

Five-year trends for automotive and industrial batteries are projected. Topic covered include: SLI shipments; lead consumption; automotive batteries (5-year annual growth rates); industrial batteries (standby power and motive power); estimated average battery life by area/country for 1989; US motor vehicle registrations; replacement battery shipments; potential lead consumption in electric vehicles; BCI recycling rates for lead-acid batteries; US average car/light truck battery life; channels of distribution; replacement battery inventory end July; 2nd US battery shipment forecast.

Brazilian policy on battery disposal and its practical effects on battery recycling

NASA Astrophysics Data System (ADS)

Crocce Romano Espinosa, Denise; Moura Bernardes, Andréa; Alberto Soares Tenório, Jorge

The disposal of batteries is a problem that has grown in the last few years, due to the increase in the use of portable devices. Batteries may contain toxic metals such as cadmium, mercury and lead, so their disposal must be controlled. Brazil was the first country in Latin America to regulate the disposal and treatment of batteries. Limits were established on the concentration of heavy metals within batteries, so that they could be disposed along with domestic waste. Since batteries are products used broadly, it is very difficult to control their disposal. In order to have an efficient collection, the population must be engaged, and that can only happen if they are informed about the laws and regulations regarding the subject, as well as the importance of disposing of batteries with higher concentrations of heavy metals or toxic substances separately from domestic garbage. Around the world, there are some long-established recycling processes for batteries. In Brazil, automotive (lead-acid) batteries have been recycled for several years, whereas the recycling of other types of batteries is just starting. This work does an analysis of the Brazilian law for battery recycling and presents some suggestions and examples of the initiatives of other countries, in order to manage of this kind of dangerous waste.

Proton enhanced dynamic battery chemistry for aprotic lithium-oxygen batteries.

PubMed

Zhu, Yun Guang; Liu, Qi; Rong, Yangchun; Chen, Haomin; Yang, Jing; Jia, Chuankun; Yu, Li-Juan; Karton, Amir; Ren, Yang; Xu, Xiaoxiong; Adams, Stefan; Wang, Qing

2017-02-06

Water contamination is generally considered to be detrimental to the performance of aprotic lithium-air batteries, whereas this view is challenged by recent contrasting observations. This has provoked a range of discussions on the role of water and its impact on batteries. In this work, a distinct battery chemistry that prevails in water-contaminated aprotic lithium-oxygen batteries is revealed. Both lithium ions and protons are found to be involved in the oxygen reduction and evolution reactions, and lithium hydroperoxide and lithium hydroxide are identified as predominant discharge products. The crystallographic and spectroscopic characteristics of lithium hydroperoxide monohydrate are scrutinized both experimentally and theoretically. Intriguingly, the reaction of lithium hydroperoxide with triiodide exhibits a faster kinetics, which enables a considerably lower overpotential during the charging process. The battery chemistry unveiled in this mechanistic study could provide important insights into the understanding of nominally aprotic lithium-oxygen batteries and help to tackle the critical issues confronted.

Proton enhanced dynamic battery chemistry for aprotic lithium–oxygen batteries

PubMed Central

Zhu, Yun Guang; Liu, Qi; Rong, Yangchun; Chen, Haomin; Yang, Jing; Jia, Chuankun; Yu, Li-Juan; Karton, Amir; Ren, Yang; Xu, Xiaoxiong; Adams, Stefan; Wang, Qing

2017-01-01

Water contamination is generally considered to be detrimental to the performance of aprotic lithium–air batteries, whereas this view is challenged by recent contrasting observations. This has provoked a range of discussions on the role of water and its impact on batteries. In this work, a distinct battery chemistry that prevails in water-contaminated aprotic lithium–oxygen batteries is revealed. Both lithium ions and protons are found to be involved in the oxygen reduction and evolution reactions, and lithium hydroperoxide and lithium hydroxide are identified as predominant discharge products. The crystallographic and spectroscopic characteristics of lithium hydroperoxide monohydrate are scrutinized both experimentally and theoretically. Intriguingly, the reaction of lithium hydroperoxide with triiodide exhibits a faster kinetics, which enables a considerably lower overpotential during the charging process. The battery chemistry unveiled in this mechanistic study could provide important insights into the understanding of nominally aprotic lithium–oxygen batteries and help to tackle the critical issues confronted. PMID:28165008

Self-Organizing Batteries

DTIC Science & Technology

2005-12-16

of these principles to a lithium ion battery , resulting in the demonstration of the first self-organized rechargeable battery. These accomplishments...spherical graphite widely used as a lithium ion battery anode, was used as the high-index endmember and was attached to an AFM cantilever. Its...resulting junctions could be stable under electrochemical conditions typical of lithium ion battery systems. We used PEG + LiClO 4 as our model solid

14. Station Control Batteries and Battery Chargers, view to the ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

14. Station Control Batteries and Battery Chargers, view to the northeast. The original battery charger is the center cabinet on the left side of photograph, with the new charger on the far left of photograph and a circuit breaker unit for the chargers is visible in the center of the photograph. The batteries are visible on three racks through the open doorway. - Washington Water Power Clark Fork River Cabinet Gorge Hydroelectric Development, Powerhouse, North Bank of Clark Fork River at Cabinet Gorge, Cabinet, Bonner County, ID

Metformin inhibits 7,12-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maayah, Zaid H.; Ghebeh, Hazem; Alhaider, Abdulqader A.

2015-04-15

Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted usingmore » 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in NAD(P)H:quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA-mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand

Chemically rechargeable battery

NASA Technical Reports Server (NTRS)

Graf, James E. (Inventor); Rowlette, John J. (Inventor)

1984-01-01

Batteries (50) containing oxidized, discharged metal electrodes such as an iron-air battery are charged by removing and storing electrolyte in a reservoir (98), pumping fluid reductant such as formalin (aqueous formaldehyde) from a storage tank (106) into the battery in contact with the surfaces of the electrodes. After sufficient iron hydroxide has been reduced to iron, the spent reductant is drained, the electrodes rinsed with water from rinse tank (102) and then the electrolyte in the reservoir (106) is returned to the battery. The battery can be slowly electrically charged when in overnight storage but can be quickly charged in about 10 minutes by the chemical procedure of the invention.

The crystal structure of the AhRR-ARNT heterodimer reveals the structural basis of the repression of AhR-mediated transcription.

PubMed

Sakurai, Shunya; Shimizu, Toshiyuki; Ohto, Umeharu

2017-10-27

2,3,7,8-Tetrachlorodibenzo- p -dioxin and related compounds are extraordinarily potent environmental toxic pollutants. Most of the 2,3,7,8-tetrachlorodibenzo- p -dioxin toxicities are mediated by aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor belonging to the basic helix-loop-helix (bHLH) Per-ARNT-Sim (PAS) family. Upon ligand binding, AhR forms a heterodimer with AhR nuclear translocator (ARNT) and induces the expression of genes involved in various biological responses. One of the genes induced by AhR encodes AhR repressor (AhRR), which also forms a heterodimer with ARNT and represses the activation of AhR-dependent transcription. The control of AhR activation is critical for managing AhR-mediated diseases, but the mechanisms by which AhRR represses AhR activation remain poorly understood, because of the lack of structural information. Here, we determined the structure of the AhRR-ARNT heterodimer by X-ray crystallography, which revealed an asymmetric intertwined domain organization presenting structural features that are both conserved and distinct among bHLH-PAS family members. The structures of AhRR-ARNT and AhR-ARNT were similar in the bHLH-PAS-A region, whereas the PAS-B of ARNT in the AhRR-ARNT complex exhibited a different domain arrangement in this family reported so far. The structure clearly disclosed that AhRR competitively represses AhR binding to ARNT and target DNA and further suggested the existence of an AhRR-ARNT-specific repression mechanism. This study provides a structural basis for understanding the mechanism by which AhRR represses AhR-mediated gene transcription. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Solar-rechargeable battery based on photoelectrochemical water oxidation: Solar water battery.

PubMed

Kim, Gonu; Oh, Misol; Park, Yiseul

2016-09-15

As an alternative to the photoelectrochemical water splitting for use in the fuel cells used to generate electrical power, this study set out to develop a solar energy rechargeable battery system based on photoelectrochemical water oxidation. We refer to this design as a "solar water battery". The solar water battery integrates a photoelectrochemical cell and battery into a single device. It uses a water oxidation reaction to simultaneously convert and store solar energy. With the solar water battery, light striking the photoelectrode causes the water to be photo-oxidized, thus charging the battery. During the discharge process, the solar water battery reduces oxygen to water with a high coulombic efficiency (>90%) and a high average output voltage (0.6 V). Because the reduction potential of oxygen is more positive [E(0) (O2/H2O) = 1.23 V vs. NHE] than common catholytes (e.g., iodide, sulfur), a high discharge voltage is produced. The solar water battery also exhibits a superior storage ability, maintaining 99% of its specific discharge capacitance after 10 h of storage, without any evidence of self-discharge. The optimization of the cell design and configuration, taking the presence of oxygen in the cell into account, was critical to achieving an efficient photocharge/discharge.

77 FR 39321 - Eighth Meeting: RTCA Special Committee 225, Rechargeable Lithium Battery and Battery Systems...

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2012-07-02

... Committee 225, Rechargeable Lithium Battery and Battery Systems--Small and Medium Sizes AGENCY: Federal... Special Committee 225, Rechargeable Lithium Battery and Battery Systems--Small and Medium Sizes. SUMMARY... 225, Rechargeable Lithium Battery and Battery Systems--Small and Medium Sizes. DATES: The meeting will...

78 FR 6845 - Eleventh Meeting: RTCA Special Committee 225, Rechargeable Lithium Battery and Battery Systems...

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2013-01-31

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78 FR 16031 - Twelfth Meeting: RTCA Special Committee 225, Rechargeable Lithium Battery and Battery Systems...

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2013-03-13

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78 FR 55773 - Fourteenth Meeting: RTCA Special Committee 225, Rechargeable Lithium Battery and Battery Systems...

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2013-09-11

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78 FR 38093 - Thirteenth Meeting: RTCA Special Committee 225, Rechargeable Lithium Battery and Battery Systems...

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2013-06-25

... Committee 225, Rechargeable Lithium Battery and Battery Systems--Small and Medium Size AGENCY: Federal... Special Committee 225, Rechargeable Lithium Battery and Battery Systems--Small and Medium Size. SUMMARY... Committee 225, Rechargeable Lithium Battery and Battery Systems--Small and Medium Size. DATES: The meeting...

CYP1A1, GCLC, AGT, AGTR1 gene-gene interactions in community-acquired pneumonia pulmonary complications.

PubMed

Salnikova, Lyubov E; Smelaya, Tamara V; Golubev, Arkadiy M; Rubanovich, Alexander V; Moroz, Viktor V

2013-11-01

This study was conducted to establish the possible contribution of functional gene polymorphisms in detoxification/oxidative stress and vascular remodeling pathways to community-acquired pneumonia (CAP) susceptibility in the case-control study (350 CAP patients, 432 control subjects) and to predisposition to the development of CAP complications in the prospective study. All subjects were genotyped for 16 polymorphic variants in the 14 genes of xenobiotics detoxification CYP1A1, AhR, GSTM1, GSTT1, ABCB1, redox-status SOD2, CAT, GCLC, and vascular homeostasis ACE, AGT, AGTR1, NOS3, MTHFR, VEGFα. Risk of pulmonary complications (PC) in the single locus analysis was associated with CYP1A1, GCLC and AGTR1 genes. Extra PC (toxic shock syndrome and myocarditis) were not associated with these genes. We evaluated gene-gene interactions using multi-factor dimensionality reduction, and cumulative gene risk score approaches. The final model which included >5 risk alleles in the CYP1A1 (rs2606345, rs4646903, rs1048943), GCLC, AGT, and AGTR1 genes was associated with pleuritis, empyema, acute respiratory distress syndrome, all PC and acute respiratory failure (ARF). We considered CYP1A1, GCLC, AGT, AGTR1 gene set using Set Distiller mode implemented in GeneDecks for discovering gene-set relations via the degree of sharing descriptors within a given gene set. N-acetylcysteine and oxygen were defined by Set Distiller as the best descriptors for the gene set associated in the present study with PC and ARF. Results of the study are in line with literature data and suggest that genetically determined oxidative stress exacerbation may contribute to the progression of lung inflammation.

77 FR 8325 - Sixth Meeting: RTCA Special Committee 225, Rechargeable Lithium Batteries and Battery Systems...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-14

... 225, Rechargeable Lithium Batteries and Battery Systems, Small and Medium Size AGENCY: Federal... Committee 225, Rechargeable Lithium Batteries and Battery Systems, Small and Medium Size. SUMMARY: The FAA..., Rechargeable Lithium Batteries and Battery Systems, Small and Medium Size. DATES: The meeting will be held...

Alkaline quinone flow battery.

PubMed

Lin, Kaixiang; Chen, Qing; Gerhardt, Michael R; Tong, Liuchuan; Kim, Sang Bok; Eisenach, Louise; Valle, Alvaro W; Hardee, David; Gordon, Roy G; Aziz, Michael J; Marshak, Michael P

2015-09-25

Storage of photovoltaic and wind electricity in batteries could solve the mismatch problem between the intermittent supply of these renewable resources and variable demand. Flow batteries permit more economical long-duration discharge than solid-electrode batteries by using liquid electrolytes stored outside of the battery. We report an alkaline flow battery based on redox-active organic molecules that are composed entirely of Earth-abundant elements and are nontoxic, nonflammable, and safe for use in residential and commercial environments. The battery operates efficiently with high power density near room temperature. These results demonstrate the stability and performance of redox-active organic molecules in alkaline flow batteries, potentially enabling cost-effective stationary storage of renewable energy. Copyright © 2015, American Association for the Advancement of Science.

77 FR 20688 - Seventh Meeting: RTCA Special Committee 225, Rechargeable Lithium Batteries and Battery Systems...

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2012-04-05

... Committee 225, Rechargeable Lithium Batteries and Battery Systems, Small and Medium Size AGENCY: Federal... Committee 225, Rechargeable Lithium Batteries and Battery Systems, Small and Medium Size. SUMMARY: The FAA..., Rechargeable Lithium Batteries and Battery Systems, Small and Medium Size. DATES: The meeting will be held May...

76 FR 22161 - Second Meeting: RTCA Special Committee 225: Rechargeable Lithium Batteries and Battery Systems...

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2011-04-20

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76 FR 6180 - First Meeting: RTCA Special Committee 225: Rechargeable Lithium Batteries and Battery Systems...

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2011-02-03

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76 FR 54527 - Fourth Meeting: RTCA Special Committee 225: Rechargeable Lithium Batteries and Battery Systems...

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2011-09-01

... Committee 225: Rechargeable Lithium Batteries and Battery Systems--Small and Medium Sizes AGENCY: Federal... Lithium Batteries and Battery Systems--Small and Medium Sizes. SUMMARY: The FAA is issuing this notice to advise the public of a meeting of RTCA Special Committee 225: Rechargeable Lithium Batteries and Battery...

76 FR 38741 - Third Meeting: RTCA Special Committee 225: Rechargeable Lithium Batteries and Battery Systems...

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2011-07-01

... 225: Rechargeable Lithium Batteries and Battery Systems--Small and Medium Sizes AGENCY: Federal... Lithium Batteries and Battery Systems--Small and Medium Sizes. SUMMARY: The FAA is issuing this notice to advise the public of a meeting of RTCA Special Committee 225: Rechargeable Lithium Batteries and Battery...

75 FR 63 - Hazardous Materials: Revision to Requirements for the Transportation of Batteries and Battery...

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2010-01-04

... 2137-AE54 Hazardous Materials: Revision to Requirements for the Transportation of Batteries and Battery... batteries and battery-powered devices. This final rule corrects several errors in the January 14, 2009 final... batteries and battery-powered devices. This final rule corrects several errors in the final rule. Because...

The aryl hydrocarbon receptor and estrogen receptor alpha differentially modulate nuclear factor erythroid-2-related factor 2 transactivation in MCF-7 breast cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lo, Raymond; Matthews, Jason, E-mail: jason.matthews@utoronto.ca

2013-07-15

Nuclear factor erythroid-2-related factor 2 (NRF2; NFE2L2) plays an important role in mediating cellular protection against reactive oxygen species. NRF2 signaling is positively modulated by the aryl hydrocarbon receptor (AHR) but inhibited by estrogen receptor alpha (ERα). In this study we investigated the crosstalk among NRF2, AHR and ERα in MCF-7 breast cancer cells treated with the NRF2 activator sulforaphane (SFN), a dual AHR and ERα activator, 3,3′-diindolylmethane (DIM), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 17β-estradiol (E2). SFN-dependent increases in NADPH-dependent oxidoreductase 1 (NQO1) and heme oxygenase I (HMOX1) mRNA levels were significantly reduced after co-treatment with E2. E2-dependent repression of NQO1 andmore » HMOX1 was associated with increased ERα but reduced p300 recruitment and reduced histone H3 acetylation at both genes. In contrast, DIM + SFN or TCDD + SFN induced NQO1 and HMOX1 mRNA expression to levels higher than SFN alone, which was prevented by RNAi-mediated knockdown of AHR. DIM + SFN but not TCDD + SFN also induced recruitment of ERα to NQO1 and HMOX1. However, the presence of AHR at NQO1 and HMOX1 restored p300 recruitment and histone H3 acetylation, thereby reversing the ERα-dependent repression of NRF2. Taken together, our study provides further evidence of functional interplay among NRF2, AHR and ERα signaling pathways through altered p300 recruitment to NRF2-regulated target genes. - Highlights: • We examined crosstalk among ERα, AHR, and NRF2 in MCF-7 breast cancer cells. • AHR enhanced the mRNA expression levels of two NRF2 target genes – HMOX1 and NQO1. • ERα repressed HMOX1 and NQO1 expression via decreased histone acetylation. • AHR prevented ERα-dependent repression of HMOX1 and NQO1.« less

NASA Aerospace Flight Battery Program: Generic Safety, Handling and Qualification Guidelines for Lithium-Ion (Li-Ion) Batteries; Availability of Source Materials for Lithium-Ion (Li-Ion) Batteries; Maintaining Technical Communications Related to Aerospace Batteries (NASA Aerospace Battery Workshop). Volume 1, Part 1

NASA Technical Reports Server (NTRS)

Manzo, Michelle A.; Brewer, Jeffrey C.; Bugga, Ratnakumar V.; Darcy, Eric C.; Jeevarajan, Judith A.; McKissock, Barbara I.; Schmitz, Paul C.

2010-01-01

This NASA Aerospace Flight Battery Systems Working Group was chartered within the NASA Engineering and Safety Center (NESC). The Battery Working Group was tasked to complete tasks and to propose proactive work to address battery related, agency-wide issues on an annual basis. In its first year of operation, this proactive program addressed various aspects of the validation and verification of aerospace battery systems for NASA missions. Studies were performed, issues were discussed and in many cases, test programs were executed to generate recommendations and guidelines to reduce risk associated with various aspects of implementing battery technology in the aerospace industry. This document contains Part 1 - Volume I: Generic Safety, Handling and Qualification Guidelines for Lithium-Ion (Li-Ion) Batteries, Availability of Source Materials for Lithium-Ion (Li-Ion) Batteries, and Maintaining Technical Communications Related to Aerospace Batteries (NASA Aerospace Battery Workshop).

Strain measurement based battery testing

DOEpatents

Xu, Jeff Qiang; Steiber, Joe; Wall, Craig M.; Smith, Robert; Ng, Cheuk

2017-05-23

A method and system for strain-based estimation of the state of health of a battery, from an initial state to an aged state, is provided. A strain gauge is applied to the battery. A first strain measurement is performed on the battery, using the strain gauge, at a selected charge capacity of the battery and at the initial state of the battery. A second strain measurement is performed on the battery, using the strain gauge, at the selected charge capacity of the battery and at the aged state of the battery. The capacity degradation of the battery is estimated as the difference between the first and second strain measurements divided by the first strain measurement.

A desalination battery.

PubMed

Pasta, Mauro; Wessells, Colin D; Cui, Yi; La Mantia, Fabio

2012-02-08

Water desalination is an important approach to provide fresh water around the world, although its high energy consumption, and thus high cost, call for new, efficient technology. Here, we demonstrate the novel concept of a "desalination battery", which operates by performing cycles in reverse on our previously reported mixing entropy battery. Rather than generating electricity from salinity differences, as in mixing entropy batteries, desalination batteries use an electrical energy input to extract sodium and chloride ions from seawater and to generate fresh water. The desalination battery is comprised by a Na(2-x)Mn(5)O(10) nanorod positive electrode and Ag/AgCl negative electrode. Here, we demonstrate an energy consumption of 0.29 Wh l(-1) for the removal of 25% salt using this novel desalination battery, which is promising when compared to reverse osmosis (~ 0.2 Wh l(-1)), the most efficient technique presently available. © 2012 American Chemical Society

HR38, an ortholog of NR4A family nuclear receptors, mediates 20-hydroxyecdysone regulation of carbohydrate metabolism during mosquito reproduction.

PubMed

Dong, Dujuan; Zhang, Yang; Smykal, Vlastimil; Ling, Lin; Raikhel, Alexander S

2018-05-01

The Aedes aegypti mosquito is the principal vector for many dangerous human viral diseases. Carbohydrate metabolism (CM) is essential for supplying the energy necessary for host seeking, blood digestion and rapid egg development of this vector insect. The steroid hormone 20-hydroxyecdysone (20E) and the ecdysone receptor (EcR) are important regulators of CM, coordinating it with female reproductive events. We report here that the NR4A nuclear receptor AHR38 plays a critical role in mediating these actions of 20E and EcR. AHR38 RNA interference (RNAi) depletion in female mosquitoes blocked the transcriptional activation of CM genes encoding phosphoglucomutase (PGM) and trehalose-6-phophate synthase (TPS); it caused an increase of glycogen accumulation and a decrease of the circulating sugar trehalose. This treatment also resulted in a dramatic reduction in fecundity. Considering that these phenotypes resulting from AHR38 RNAi depletion are similar to those of EcR RNAi, we investigated a possible connection between these transcription factors in CM regulation. EcR RNAi inhibits the AHR38 gene expression. Moreover, the 20E-induced EcR complex directly activates AHR38 by binding to the ecdysone response element (EcRE) in the upstream regulatory region of this gene. The present work has implicated AHR38 in the 20E-mediated control of CM and provided new insight into mechanisms of 20E regulation of metabolism during female mosquito reproduction. © 2018 Published by Elsevier Ltd.

Battery Thermal Characterization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keyser, Matthew; Saxon, Aron; Powell, Mitchell

2016-06-07

This poster shows the progress in battery thermal characterization over the previous year. NREL collaborated with U.S. DRIVE and USABC battery developers to obtain thermal properties of their batteries, obtained heat capacity and heat generation of cells under various power profiles, obtained thermal images of the cells under various drive cycles, and used the measured results to validate thermal models. Thermal properties are used for the thermal analysis and design of improved battery thermal management systems to support achieve life and performance targets.

Solid polymer battery electrolyte and reactive metal-water battery

DOEpatents

Harrup, Mason K.; Peterson, Eric S.; Stewart, Frederick F.

2000-01-01

In one implementation, a reactive metal-water battery includes an anode comprising a metal in atomic or alloy form selected from the group consisting of periodic table Group 1A metals, periodic table Group 2A metals and mixtures thereof. The battery includes a cathode comprising water. Such also includes a solid polymer electrolyte comprising a polyphosphazene comprising ligands bonded with a phosphazene polymer backbone. The ligands comprise an aromatic ring containing hydrophobic portion and a metal ion carrier portion. The metal ion carrier portion is bonded at one location with the polymer backbone and at another location with the aromatic ring containing hydrophobic portion. The invention also contemplates such solid polymer electrolytes use in reactive metal/water batteries, and in any other battery.

Mathematical Storage-Battery Models

NASA Technical Reports Server (NTRS)

Chapman, C. P.; Aston, M.

1985-01-01

Empirical formula represents performance of electrical storage batteries. Formula covers many battery types and includes numerous coefficients adjusted to fit peculiarities of each type. Battery and load parameters taken into account include power density in battery, discharge time, and electrolyte temperature. Applications include electric-vehicle "fuel" gages and powerline load leveling.

Battery Vent Mechanism And Method

DOEpatents

Ching, Larry K. W.

2000-02-15

Disclosed herein is a venting mechanism for a battery. The venting mechanism includes a battery vent structure which is located on the battery cover and may be integrally formed therewith. The venting mechanism includes an opening extending through the battery cover such that the opening communicates with a plurality of battery cells located within the battery case. The venting mechanism also includes a vent manifold which attaches to the battery vent structure. The vent manifold includes a first opening which communicates with the battery vent structure opening and second and third openings which allow the vent manifold to be connected to two separate conduits. In this manner, a plurality of batteries may be interconnected for venting purposes, thus eliminating the need to provide separate vent lines for each battery. The vent manifold may be attached to the battery vent structure by a spin-welding technique. To facilitate this technique, the vent manifold may be provided with a flange portion which fits into a corresponding groove portion on the battery vent structure. The vent manifold includes an internal chamber which is large enough to completely house a conventional battery flame arrester and overpressure safety valve. In this manner, the vent manifold, when installed, lessens the likelihood of tampering with the flame arrester and safety valve.

Battery venting system and method

DOEpatents

Casale, Thomas J.; Ching, Larry K. W.; Baer, Jose T.; Swan, David H.

1999-01-05

Disclosed herein is a venting mechanism for a battery. The venting mechanism includes a battery vent structure which is located on the battery cover and may be integrally formed therewith. The venting mechanism includes an opening extending through the battery cover such that the opening communicates with a plurality of battery cells located within the battery case. The venting mechanism also includes a vent manifold which attaches to the battery vent structure. The vent manifold includes a first opening which communicates with the battery vent structure opening and second and third openings which allow the vent manifold to be connected to two separate conduits. In this manner, a plurality of batteries may be interconnected for venting purposes, thus eliminating the need to provide separate vent lines for each battery. The vent manifold may be attached to the battery vent structure by a spin-welding technique. To facilitate this technique, the vent manifold may be provided with a flange portion which fits into a corresponding groove portion on the battery vent structure. The vent manifold includes an internal chamber which is large enough to completely house a conventional battery flame arrester and overpressure safety valve. In this manner, the vent manifold, when installed, lessens the likelihood of tampering with the flame arrester and safety valve.

Nickel-based rechargeable batteries

NASA Astrophysics Data System (ADS)

Shukla, A. K.; Venugopalan, S.; Hariprakash, B.

Nickel-iron (Ni-Fe), nickel-cadmium (Ni-Cd), nickel-hydrogen (Ni-H 2), nickel-metal hydride (Ni-MH) and nickel-zinc (Ni-Zn) batteries employ nickel oxide electrodes as the positive plates, and are hence, categorised as nickel-based batteries. This article highlights the operating principles and advances made in these battery systems during the recent years. In particular, significant improvements have been made in the Ni-MH batteries which are slowly capturing the market occupied by the ubiquitous Ni-Cd batteries.

Hypoxia perturbs aryl hydrocarbon receptor signaling and CYP1A1 expression induced by PCB 126 in human skin and liver-derived cell lines.

PubMed

Vorrink, Sabine U; Severson, Paul L; Kulak, Mikhail V; Futscher, Bernard W; Domann, Frederick E

2014-02-01

The aryl hydrocarbon receptor (AhR) is an important mediator of toxic responses after exposure to xenobiotics including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like polychlorinated biphenyls (PCBs). Activation of AhR responsive genes requires AhR dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), a heterodimeric partner also shared by the hypoxia-inducible factor-1α (HIF-1α) protein. TCDD-stimulated AhR transcriptional activity can be influenced by hypoxia; however, it less well known whether hypoxia interferes with AhR transcriptional transactivation in the context of PCB-mediated AhR activation in human cells. Elucidation of this interaction is important in liver hepatocytes which extensively metabolize ingested PCBs and experience varying degrees of oxygen tension during normal physiologic function. This study was designed to assess the effect of hypoxia on AhR transcriptional responses after exposure to 3,3',4,4',5-pentachlorobiphenyl (PCB 126). Exposure to 1% O2 prior to PCB 126 treatment significantly inhibited CYP1A1 mRNA and protein expression in human HepG2 and HaCaT cells. CYP1A1 transcriptional activation was significantly decreased upon PCB 126 stimulation under conditions of hypoxia. Additionally, hypoxia pre-treatment reduced PCB 126 induced AhR binding to CYP1 target gene promoters. Importantly, ARNT overexpression rescued cells from the inhibitory effect of hypoxia on XRE-luciferase reporter activity. Therefore, the mechanism of interference of the signaling crosstalk between the AhR and hypoxia pathways appears to be at least in part dependent on ARNT availability. Our results show that AhR activation and CYP1A1 expression induced by PCB 126 were significantly inhibited by hypoxia and hypoxia might therefore play an important role in PCB metabolism and toxicity. Copyright © 2013 Elsevier Inc. All rights reserved.

HST Replacement Battery Initial Performance

NASA Technical Reports Server (NTRS)

Krol, Stan; Waldo, Greg; Hollandsworth, Roger

2009-01-01

The Hubble Space Telescope (HST) original Nickel-Hydrogen (NiH2) batteries were replaced during the Servicing Mission 4 (SM4) after 19 years and one month on orbit.The purpose of this presentation is to highlight the findings from the assessment of the initial sm4 replacement battery performance. The batteries are described, the 0 C capacity is reviewed, descriptions, charts and tables reviewing the State Of Charge (SOC) Performance, the Battery Voltage Performance, the battery impedance, the minimum voltage performance, the thermal performance, the battery current, and the battery system recharge ratio,

Kynurenine promotes the goblet cell differentiation of HT-29 colon carcinoma cells by modulating Wnt, Notch and AhR signals.

PubMed

Park, Joo-Hung; Lee, Jeong-Min; Lee, Eun-Jin; Kim, Da-Jeong; Hwang, Won-Bhin

2018-04-01

Various amino acids regulate cell growth and differentiation. In the present study, we examined the ability of HT-29 cells to differentiate into goblet cells in RPMI and DMEM which are largely different in the amounts of numerous amino acids. Most of the HT-29 cells differentiated into goblet cells downregulating the stem cell marker Lgr5 when cultured in DMEM, but remained undifferentiated in RPMI. The goblet cell differentiation in DMEM was inhibited by 1-methyl-tryptophan (1-MT), an inhibitor of indoleamine 2,3 dioxygenase-1 which is the initial enzyme in tryptophan metabolism along the kynurenine (KN) pathway, whereas tryptophan and KN induced goblet cell differentiation in RPMI. The levels of Notch1 and its activation product Notch intracytoplasmic domain in HT-29 cells were lower in DMEM than those in RPMI and were increased by 1-MT in both media. HT-29 cells grown in both media expressed β-catenin at the same level on day 2 when goblet cell differentiation was not observed. β-catenin expression, which was increased by 1-MT in both media, was decreased by KN. DMEM reduced Hes1 expression while enhancing Hath1 expression. Finally, aryl hydrocarbon receptor (AhR) activation moderately induced goblet cell differentiation. Our results suggest that KN promotes goblet cell differentiation by regulating Wnt, Notch, and AhR signals and expression of Hes1 and Hath1.

Battery venting system and method

DOEpatents

Casale, T.J.; Ching, L.K.W.; Baer, J.T.; Swan, D.H.

1999-01-05

Disclosed herein is a venting mechanism for a battery. The venting mechanism includes a battery vent structure which is located on the battery cover and may be integrally formed therewith. The venting mechanism includes an opening extending through the battery cover such that the opening communicates with a plurality of battery cells located within the battery case. The venting mechanism also includes a vent manifold which attaches to the battery vent structure. The vent manifold includes a first opening which communicates with the battery vent structure opening and second and third openings which allow the vent manifold to be connected to two separate conduits. In this manner, a plurality of batteries may be interconnected for venting purposes, thus eliminating the need to provide separate vent lines for each battery. The vent manifold may be attached to the battery vent structure by a spin-welding technique. To facilitate this technique, the vent manifold may be provided with a flange portion which fits into a corresponding groove portion on the battery vent structure. The vent manifold includes an internal chamber which is large enough to completely house a conventional battery flame arrester and overpressure safety valve. In this manner, the vent manifold, when installed, lessens the likelihood of tampering with the flame arrester and safety valve. 8 figs.

Comparative analysis of TCDD-induced AhR-mediated gene expression in human, mouse and rat primary B cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kovalova, Natalia, E-mail: kovalova@msu.edu

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental pollutant that activates the aryl hydrocarbon receptor (AhR) resulting in altered gene expression. In vivo, in vitro, and ex vivo studies have demonstrated that B cells are directly impaired by TCDD, and are a sensitive target as evidenced by suppression of antibody responses. The window of sensitivity to TCDD-induced suppression of IgM secretion among mouse, rat and human B cells is similar. Specifically, TCDD must be present within the initial 12 h post B cell stimulation, indicating that TCDD disrupts early signaling network(s) necessary for B lymphocyte activation and differentiation. Therefore, we hypothesized thatmore » TCDD treatment across three different species (mouse, rat and human) triggers a conserved, B cell-specific mechanism that is involved in TCDD-induced immunosuppression. RNA sequencing (RNA-Seq) was used to identify B cell-specific orthologous genes that are differentially expressed in response to TCDD in primary mouse, rat and human B cells. Time course studies identified TCDD-elicited differential expression of 515 human, 2371 mouse and 712 rat orthologous genes over the 24-h period. 28 orthologs were differentially expressed in response to TCDD in all three species. Overrepresented pathways enriched in all three species included cytokine-cytokine receptor interaction, ECM-receptor interaction, focal adhesion, regulation of actin cytoskeleton and pathways in cancer. Differentially expressed genes functionally associated with cell-cell signaling in humans, immune response in mice, and oxidation reduction in rats. Overall, these results suggest that despite the conservation of the AhR and its signaling mechanism, TCDD elicits species-specific gene expression changes. - Highlights: • Kovalova TAAP Highlights Nov. 2016 • RNA-Seq identified TCDD-induced gene expression in PWM-activated primary B cells. • TCDD elicited differential expression of 515 human, 2371 mouse

77 FR 56253 - Ninth Meeting: RTCA Special Committee 225, Rechargeable Lithium Battery and Battery Systems-Small...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-12

... 225, Rechargeable Lithium Battery and Battery Systems--Small and Medium Size AGENCY: Federal Aviation... 225, Rechargeable Lithium Battery and Battery Systems--Small and Medium Size. SUMMARY: The FAA is..., Rechargeable Lithium Battery and Battery Systems--Small and Medium Size. DATES: The meeting will be held...

77 FR 66084 - Tenth Meeting: RTCA Special Committee 225, Rechargeable Lithium Battery and Battery Systems-Small...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-01

... 225, Rechargeable Lithium Battery and Battery Systems--Small and Medium Size AGENCY: Federal Aviation... 225, Rechargeable Lithium Battery and Battery Systems--Small and Medium Size. SUMMARY: The FAA is..., Rechargeable Lithium Battery and Battery Systems--Small and Medium Size. DATES: The meeting will be held...

All-graphene-battery: bridging the gap between supercapacitors and lithium ion batteries

NASA Astrophysics Data System (ADS)

Kim, Haegyeom; Park, Kyu-Young; Hong, Jihyun; Kang, Kisuk

2014-06-01

Herein, we propose an advanced energy-storage system: all-graphene-battery. It operates based on fast surface-reactions in both electrodes, thus delivering a remarkably high power density of 6,450 W kg-1total electrode while also retaining a high energy density of 225 Wh kg-1total electrode, which is comparable to that of conventional lithium ion battery. The performance and operating mechanism of all-graphene-battery resemble those of both supercapacitors and batteries, thereby blurring the conventional distinction between supercapacitors and batteries. This work demonstrates that the energy storage system made with carbonaceous materials in both the anode and cathode are promising alternative energy-storage devices.

All-graphene-battery: bridging the gap between supercapacitors and lithium ion batteries.

PubMed

Kim, Haegyeom; Park, Kyu-Young; Hong, Jihyun; Kang, Kisuk

2014-06-13

Herein, we propose an advanced energy-storage system: all-graphene-battery. It operates based on fast surface-reactions in both electrodes, thus delivering a remarkably high power density of 6,450 W kg(-1)(total electrode) while also retaining a high energy density of 225 Wh kg(-1)(total electrode), which is comparable to that of conventional lithium ion battery. The performance and operating mechanism of all-graphene-battery resemble those of both supercapacitors and batteries, thereby blurring the conventional distinction between supercapacitors and batteries. This work demonstrates that the energy storage system made with carbonaceous materials in both the anode and cathode are promising alternative energy-storage devices.

Concept of AHRS Algorithm Designed for Platform Independent Imu Attitude Alignment

NASA Astrophysics Data System (ADS)

Tomaszewski, Dariusz; Rapiński, Jacek; Pelc-Mieczkowska, Renata

2017-12-01

Nowadays, along with the advancement of technology one can notice the rapid development of various types of navigation systems. So far the most popular satellite navigation, is now supported by positioning results calculated with use of other measurement system. The method and manner of integration will depend directly on the destination of system being developed. To increase the frequency of readings and improve the operation of outdoor navigation systems, one will support satellite navigation systems (GPS, GLONASS ect.) with inertial navigation. Such method of navigation consists of several steps. The first stage is the determination of initial orientation of inertial measurement unit, called INS alignment. During this process, on the basis of acceleration and the angular velocity readings, values of Euler angles (pitch, roll, yaw) are calculated allowing for unambiguous orientation of the sensor coordinate system relative to external coordinate system. The following study presents the concept of AHRS (Attitude and heading reference system) algorithm, allowing to define the Euler angles.The study were conducted with the use of readings from low-cost MEMS cell phone sensors. Subsequently the results of the study were analyzed to determine the accuracy of featured algorithm. On the basis of performed experiments the legitimacy of developed algorithm was stated.

Nonleaking battery terminals.

NASA Technical Reports Server (NTRS)

Snider, W. E.; Nagle, W. J.

1972-01-01

Three different terminals were designed for usage in a 40 ampere/hour silver zinc battery which has a 45% KOH by weight electrolyte in a plastic battery case. Life tests, including thermal cycling, electrical charge and discharge for up to three years duration, were conducted on these three different terminal designs. Tests for creep rate and tensile strength were conducted on the polyphenylene oxide plastic battery cases. Some cases were unused and others containing KOH electrolyte were placed on life tests. The design and testing of nonleaking battery terminals for use with a KOH electrolyte in a plastic case are considered.

Silicon Carbide Radioisotope Batteries

NASA Technical Reports Server (NTRS)

Rybicki, George C.

2005-01-01

The substantial radiation resistance and large bandgap of SiC semiconductor materials makes them an attractive candidate for application in a high efficiency, long life radioisotope battery. To evaluate their potential in this application, simulated batteries were constructed using SiC diodes and the alpha particle emitter Americium Am-241 or the beta particle emitter Promethium Pm-147. The Am-241 based battery showed high initial power output and an initial conversion efficiency of approximately 16%, but the power output decayed 52% in 500 hours due to radiation damage. In contrast the Pm-147 based battery showed a similar power output level and an initial conversion efficiency of approximately 0.6%, but no degradation was observed in 500 hours. However, the Pm-147 battery required approximately 1000 times the particle fluence as the Am-242 battery to achieve a similar power output. The advantages and disadvantages of each type of battery and suggestions for future improvements will be discussed.

The 1975 GSFC Battery Workshop

NASA Technical Reports Server (NTRS)

1975-01-01

The proceedings of the 1975 Goddard Space Flight Center Battery Workshop are presented. The major topics of discussion were nickel cadmium batteries and, to a lesser extent, nickel hydrogen batteries. Battery design, manufacturing techniques, testing programs, and electrochemical characteristics were considered. The utilization of these batteries for spacecraft power supplies was given particular attention.

Battery thermal management unit

NASA Astrophysics Data System (ADS)

Sanders, Nicholas A.

1989-03-01

A battery warming device has been designed which uses waste heat from an operating internal combustion engine to warm a battery. A portion of the waste heat is stored in the sensible and latent heat of a phase change type material for use in maintaining the battery temperature after the engine is shut off. The basic design of the device consists of a Phase Change Material (PCM) reservoir and a simple heat exchanger connected to the engineer's cooling system. Two types of units were built, tested and field trialed. A strap-on type which was strapped to the side of an automotive battery and was intended for the automotive after-market and a tray type on which a battery or batteries sat. This unit was intended for the heavy duty truck market. It was determined that both types of units increased the average cranking power of the batteries they were applied to. Although there were several design problems with the units such as the need for an automatic thermostatically controlled bypass valve, the overall feeling is that there is a market opportunity for both the strap-on and tray type battery warming units.

A Pulsed Power System Design Using Lithium-ion Batteries and One Charger per Battery

DTIC Science & Technology

2009-12-01

zinc-bromine and vanadium redox batteries • NAS: high-temperature sodium batteries • EDLC: Electric Double-Layer Capacitors • SMES...terminology used in this figure. • Conventional: lead-acid, nickel-cadmium, and nickel-metal hydride batteries . • Lithium: lithium ion batteries . • Flow ...than the second stage due to less current flowing to the battery [5], [7], [8], [9]. Figure 4 shows typical current, voltage, and capacity curves

Proton enhanced dynamic battery chemistry for aprotic lithium–oxygen batteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Yun Guang; Liu, Qi; Rong, Yangchun

Water is generally considered to be deteriorating to the performance of aprotic Li-air batteries, while it is challenged by the disparate effects observed recently. This has provoked a range of discussion on the role of water and its impact on the battery operation. In this work, a distinct battery chemistry that prevails in water-contaminated aprotic Li-O 2 batteries was discovered. Both lithium ions and protons were found to be involved in the oxygen reduction (ORR) and evolution reactions (OER), and LiOOH and LiOH were identified as predominant materials in the discharge product. As a new lithium compound, the crystallographic andmore » spectroscopic characteristics of LiOOH∙H 2O were scrutinized both experimentally and theoretically. The structure of LiOOH∙H 2O was found to be closely related to that of LiOH∙H 2O implying a fast conversion kinetics between the two phases. Intriguingly, LiOOH∙H 2O exhibits superior dynamic property towards the reaction with I 3 -, which renders considerably lower overpotential during the charging process. We anticipate that the new battery chemistry unveiled in this mechanistic study would provide important insights to the understanding of nominally aprotic Li-O 2 batteries and help to tackle the critical issues confronted.« less

Proton enhanced dynamic battery chemistry for aprotic lithium–oxygen batteries

DOE PAGES

Zhu, Yun Guang; Liu, Qi; Rong, Yangchun; ...

2017-02-06

Water is generally considered to be deteriorating to the performance of aprotic Li-air batteries, while it is challenged by the disparate effects observed recently. This has provoked a range of discussion on the role of water and its impact on the battery operation. In this work, a distinct battery chemistry that prevails in water-contaminated aprotic Li-O 2 batteries was discovered. Both lithium ions and protons were found to be involved in the oxygen reduction (ORR) and evolution reactions (OER), and LiOOH and LiOH were identified as predominant materials in the discharge product. As a new lithium compound, the crystallographic andmore » spectroscopic characteristics of LiOOH∙H 2O were scrutinized both experimentally and theoretically. The structure of LiOOH∙H 2O was found to be closely related to that of LiOH∙H 2O implying a fast conversion kinetics between the two phases. Intriguingly, LiOOH∙H 2O exhibits superior dynamic property towards the reaction with I 3 -, which renders considerably lower overpotential during the charging process. We anticipate that the new battery chemistry unveiled in this mechanistic study would provide important insights to the understanding of nominally aprotic Li-O 2 batteries and help to tackle the critical issues confronted.« less

Dendritic cells provide a potential link between smoking and inflammation in rheumatoid arthritis

PubMed Central

2012-01-01

Introduction Smoking increases the risk of developing rheumatoid arthritis (RA) and affects the severity of established RA. Smoking can impact on Th17 lymphocyte differentiation and function through activation of the aryl hydrocarbon receptor (AHR), a process with implications for the pathogenic mechanisms in RA that involve the cytokine, interleukin (IL)-17A. The objective of this study was to establish any effect of smoking on the inflammatory tissue lesions of rheumatoid arthritis via the AHR and IL-17A. Methods Twenty synovial and eighteen subcutaneous nodule tissue samples from 31 patients with RA were studied. Patient smoking status at the time of tissue collection was established. Expression of AHR, CYP1A1, AHRR, IL6, IL17A, IL17F, IL22, IL23, IL23R, IFNG, TBX21, IDO1 and FOXP3 genes were assessed in tissues and cultured cells using real-time PCR. Two-colour immunofluorescence was used to co-localise AHR and CYP1A1 protein in synovial tissues. The response of monocytes and monocyte-derived dendritic cells (mo-DCs) to the AHR agonist, benzo(a)pyrene (BaP) was compared in vitro. Results AHR gene expression was demonstrated in rheumatoid synovial tissues and nodules with significantly greater expression in synovia. Expression was not influenced by smoking in either tissue. Evidence of AHR activation, indicated by CYP1A1 and AHRR gene expression, was found only in synovia from patients who smoked. However, IL17A gene expression was lower in synovia from smokers. TBX21 and FOXP3 expression was not affected by smoking. Within the synovial tissues of smokers the principal cell type with evidence of AHR activation was a subset of synovial DCs. This observation was consistent with the sensitivity of human mo-DCs to BaP stimulation demonstrated in vitro. Exposure to BaP affected mo-DC function as demonstrated by decreased IL6 expression induced by PolyI:C, without affecting indoleamine 2,3 dioxygenase (IDO)1 expression. Conclusion Our findings show that one effect of

All-graphene-battery: bridging the gap between supercapacitors and lithium ion batteries

PubMed Central

Kim, Haegyeom; Park, Kyu-Young; Hong, Jihyun; Kang, Kisuk

2014-01-01

Herein, we propose an advanced energy-storage system: all-graphene-battery. It operates based on fast surface-reactions in both electrodes, thus delivering a remarkably high power density of 6,450 W kg−1total electrode while also retaining a high energy density of 225 Wh kg−1total electrode, which is comparable to that of conventional lithium ion battery. The performance and operating mechanism of all-graphene-battery resemble those of both supercapacitors and batteries, thereby blurring the conventional distinction between supercapacitors and batteries. This work demonstrates that the energy storage system made with carbonaceous materials in both the anode and cathode are promising alternative energy-storage devices. PMID:24923290

Solar-rechargeable battery based on photoelectrochemical water oxidation: Solar water battery

PubMed Central

Kim, Gonu; Oh, Misol; Park, Yiseul

2016-01-01

As an alternative to the photoelectrochemical water splitting for use in the fuel cells used to generate electrical power, this study set out to develop a solar energy rechargeable battery system based on photoelectrochemical water oxidation. We refer to this design as a “solar water battery”. The solar water battery integrates a photoelectrochemical cell and battery into a single device. It uses a water oxidation reaction to simultaneously convert and store solar energy. With the solar water battery, light striking the photoelectrode causes the water to be photo-oxidized, thus charging the battery. During the discharge process, the solar water battery reduces oxygen to water with a high coulombic efficiency (>90%) and a high average output voltage (0.6 V). Because the reduction potential of oxygen is more positive [E0 (O2/H2O) = 1.23 V vs. NHE] than common catholytes (e.g., iodide, sulfur), a high discharge voltage is produced. The solar water battery also exhibits a superior storage ability, maintaining 99% of its specific discharge capacitance after 10 h of storage, without any evidence of self-discharge. The optimization of the cell design and configuration, taking the presence of oxygen in the cell into account, was critical to achieving an efficient photocharge/discharge. PMID:27629362

An alcohol withdrawal test battery measuring multiple behavioral symptoms in mice.

PubMed

Metten, Pamela; Schlumbohm, Jason P; Huang, Lawrence C; Greenberg, Gian D; Hack, Wyatt R; Spence, Stephanie E; Crabbe, John C

2018-05-01

Despite acceptance that risk for alcohol-use disorder (AUD) has a large genetic component, the identification of genes underlying various components of risk for AUD has been hampered in humans, in part by the heterogeneity of expression of the phenotype. One aspect of AUD is physical dependence. Alcohol withdrawal is a serious consequence of alcohol dependence with multiple symptoms, many of which are seen in multiple species, and can be experienced over a wide-ranging time course. In the present three studies, we developed a battery of withdrawal tests in mice, examining behavioral symptoms from multiple domains that could be measured over time. To permit eventual use of the battery in different strains of mice, we used male and female mice of a genetically heterogeneous stock developed from intercrossing eight inbred strains. Withdrawal symptoms were assessed using commonly used tests after administration of ethanol in vapor for 72 continuous hours. We found significant effects of ethanol withdrawal versus air-breathing controls on nearly all symptoms, spanning 4 days following ethanol vapor inhalation. Withdrawal produced hypothermia, greater neurohyperexcitability (seizures and tremor), anxiety-like behaviors using an apparatus (such as reduced transitions between light and dark compartments), anhedonia (reduced sucrose preference), Straub tail, backward walking, and reductions in activity; however, there were no changes in thermal pain sensitivity, hyper-reactivity to handling, or anxiety-like emergence behaviors in other apparatus. Using these data, we constructed a refined battery of withdrawal tests. Individual differences in severity of withdrawal among different tests were weakly correlated at best. This battery should be useful for identifying genetic influences on particular withdrawal behaviors, which should reflect the influences of different constellations of genes. Published by Elsevier Inc.

Nonleaking battery terminals

NASA Technical Reports Server (NTRS)

Snider, W. E.; Nagle, W. J.

1972-01-01

Three different terminals were designed for usage in a 40 ampere/hour silver zinc battery which has a 45 percent KOH by weight electrolyte in a plastic battery case. Life tests, including thermal cycling, electrical charge and discharge for up to three years duration, were conducted on these three different terminal designs. Tests for creep rate and tensile strength were conducted on the polyphenylene oxide (PPO) plastic battery cases. Some cases were unused and others containing KOH electrolyte were placed on life tests. The design and testing of nonleaking battery terminals for use with a potassium hydroxide (KOH) electrolyte in a plastic case are discussed.

Advanced Thermal Batteries.

DTIC Science & Technology

1981-06-01

ADVANCED THERMAL BATTERIES NATIONAL UNION ELECTRIC CORPORATION ADVANCE SCIENCE DIVISION 1201 E. BELL STREET BLXXMINGTON, ILLINOIS 61701 JUNE 1981...December 1978 in: " Advanced Thermal Batteries " AFAPL-TR-78-114 Air Force Aero Propulsion Laboratory Air Force Wright Aeronautical Laboratories Air Force...March 1980 in: " Advanced Thermal Batteries " AFAPL-TR-80-2017 Air Force Aero Propulsion Laboratory Air Force Wright Aeronautical Laboratories Air Force

Norisoboldine, a natural AhR agonist, promotes Treg differentiation and attenuates colitis via targeting glycolysis and subsequent NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway.

PubMed

Lv, Qi; Wang, Kai; Qiao, Simiao; Yang, Ling; Xin, Yirong; Dai, Yue; Wei, Zhifeng

2018-02-15

Norisoboldine (NOR), a natural aryl hydrocarbon receptor (AhR) agonist, has been demonstrated to attenuate ulcerative colitis (UC) and induce the generation of Treg cells. Under UC condition, hypoxia widely exists in colonic mucosa, and secondary changes of microRNAs (miRs) expressions and glycolysis contribute to Treg differentiation. At present, we worked for exploring the deep mechanisms for NOR-promoted Treg differentiation in hypoxia and its subsequent anti-UC action from the angle of AhR/miR or AhR/glycolysis axis. Results showed that NOR promoted Treg differentiation in hypoxia and the effect was stronger relative to normoxia. It activated AhR in CD4 + T cells under hypoxic microenvironment; CH223191 (a specific AhR antagonist) and siAhR-3 abolished NOR-promoted Treg differentiation. Furthermore, the progress of glycolysis, levels of Glut1 and HK2, and expression of miR-31 rather than miR-219 and miR-490 in CD4 + T cells were downregulated by NOR treatment under hypoxic microenvironment. However, HK2 plasmid but not miR-31 mimic significantly interfered NOR-enhanced Treg polarization. In addition, NOR reduced NAD + and SIRT1 levels, facilitated the ubiquitin-proteasomal degradation of SUV39H1 protein, and inhibited the enrichment of H3K9me3 at -1, 201 to -1,500 region of Foxp3 promoter in CD4 + T cells under hypoxic microenvironment, which was weakened by HK2 plasmid, CH223191, and siAhR-3. Finally, the correlation between NOR-mediated activation of AhR, repression of glycolysis, regulation of NAD + /SIRT1/SUV39H1/H3K9me3 signals, induction of Treg cells, and remission of colitis was confirmed in mice with DSS-induced colitis by using CH223191 and HK2 plasmid. In conclusion, NOR promoted Treg differentiation and then alleviated the development of colitis by regulating AhR/glycolysis axis and subsequent NAD + /SIRT1/SUV39H1/H3K9me3 signaling pathway.

Behavior data of battery and battery pack SOC estimation under different working conditions.

PubMed

Zhang, Xu; Wang, Yujie; Yang, Duo; Chen, Zonghai

2016-12-01

This article provides the dataset of operating conditions of battery behavior. The constant current condition and the dynamic stress test (DST) condition were carried out to analyze the battery discharging and charging features. The datasets were achieved at room temperature, in April, 2016. The shared data contributes to clarify the battery pack state-of-charge (SOC) and the battery inconsistency, which is also shown in the article of "An on-line estimation of battery pack parameters and state-of-charge using dual filters based on pack model" (X. Zhang, Y. Wang, D. Yang, et al., 2016) [1].

Electric vehicle battery research and development

NASA Technical Reports Server (NTRS)

Schwartz, H. J.

1973-01-01

High energy battery technology for electric vehicles is reviewed. The state-of-the-art in conventional batteries, metal-gas batteries, alkali-metal high temperature batteries, and organic electrolyte batteries is reported.

The chlorinated AHR ligand 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) promotes reactive oxygen species (ROS) production during embryonic development in the killifish (Fundulus heteroclitus)

USGS Publications Warehouse

Arzuaga, Xabier; Wassenberg, Deena; Giulio, Richard D.; Elskus, Adria

2006-01-01

Exposure to dioxin-like chemicals that activate the aryl hydrocarbon receptor (AHR) can result in increased cellular and tissue production of reactive oxygen species (ROS). Little is known of these effects during early fish development. We used the fish model, Fundulus heteroclitus, to determine if the AHR ligand and pro-oxidant 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) can increase ROS production during killifish development, and to test a novel method for measuring ROS non-invasively in a living organism. The superoxide-sensitive fluorescent dye, dihydroethidium (DHE), was used to detect in ovo ROS production microscopically in developing killifish exposed to PCB126 or vehicle. Both in ovo CYP1A activity (ethoxyresorufin-o-deethylase, EROD) and in ovo ROS were induced by PCB126. In ovo CYP1A activity was inducible by PCB126 concentrations as low as 0.003 nM, with maximal induction occurring at 0.3 nM PCB126. These PCB126 concentrations also significantly increased in ovo ROS production in embryonic liver, ROS being detectable as early as 5 days post-fertilization. These data demonstrate that the pro-oxidant and CYP1A inducer, PCB126, increases both CYP1A activity and ROS production in developing killifish embryos. The superoxide detection assay (SoDA) described in this paper provides a semi-quantitative, easily measured, early indicator of altered ROS production that can be used in conjunction with simultaneous in ovo measurements of CYP1A activity and embryo development to explore functional relationships among biochemical, physiological and developmental responses to AHR ligands.

Micro Calorimeter for Batteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Santhanagopalan, Shriram

2017-08-01

As battery technology forges ahead and consumer demand for safer, more affordable, high-performance batteries grows, the National Renewable Energy Laboratory (NREL) has added a patented Micro Calorimeter to its existing family of R&D 100 Award-winning Isothermal Battery Calorimeters (IBCs). The Micro Calorimeter examines the thermal signature of battery chemistries early on in the design cycle using popular coin cell and small pouch cell designs, which are simple to fabricate and study.

Battery Control Boards for Li-Ion Batteries on Mars Exploration Rovers

NASA Technical Reports Server (NTRS)

Ewell, R.; Ratnakumar, B. V.; Smart, M.; Chin, K. B.; Whitcanack, L.; Narayanan, S. R.; Surampudi, S.

2006-01-01

Rechargeable Lithium-ion batteries have been operating successfully on both Spirit and Opportunity rovers for the last two years, which includes six months of Assembly Launch and Test Operations (ATLO), seven months of cruise and about eleven months of surface operations. The Battery Control Boards designed and fabricated in-house would protect cells against overcharge and over-discharge and provide cell balance. Their performance has thus far been quite satisfactory. The ground data o the mission simulation battery project little capacity loss of less than 3% during cruise and 180 sols. Batteries are poised to extend the mission beyond six months, if not a couple of years.

NASA/Marshall's lithium battery applications

NASA Technical Reports Server (NTRS)

Paschal, L. E.

1980-01-01

A general lithium battery is described and a summary of lithium battery applications is presented. Four aspects of a particular lithium battery, the inducement environmental contamination monitoring battery, are discussed-design and construction details, thermal vacuum tests, projection tests, and acceptance tests.

The 2004 NASA Aerospace Battery Workshop

NASA Technical Reports Server (NTRS)

2006-01-01

Topics covered include: Super NiCd(TradeMark) Energy Storage for Gravity Probe-B Relativity Mission; Hubble Space Telescope 2004 Battery Update; The Development of Hermetically Sealed Aerospace Nickel-Metal Hydride Cell; Serial Charging Test on High Capacity Li-Ion Cells for the Orbiter Advanced Hydraulic Power System; Cell Equalization of Lithium-Ion Cells; The Long-Term Performance of Small-Cell Batteries Without Cell-Balancing Electronics; Identification and Treatment of Lithium Battery Cell Imbalance under Flight Conditions; Battery Control Boards for Li-Ion Batteries on Mars Exploration Rovers; Cell Over Voltage Protection and Balancing Circuit of the Lithium-Ion Battery; Lithium-Ion Battery Electronics for Aerospace Applications; Lithium-Ion Cell Charge Control Unit; Lithium Ion Battery Cell Bypass Circuit Test Results at the U.S. Naval Research Laboratory; High Capacity Battery Cell By-Pass Switches: High Current Pulse Testing of Lithium-Ion; Battery By-Pass Switches to Verify Their Ability to Withstand Short-Circuits; Incorporation of Physics-Based, Spatially-Resolved Battery Models into System Simulations; A Monte Carlo Model for Li-Ion Battery Life Projections; Thermal Behavior of Large Lithium-Ion Cells; Thermal Imaging of Aerospace Battery Cells; High Rate Designed 50 Ah Li-Ion Cell for LEO Applications; Evaluation of Corrosion Behavior in Aerospace Lithium-Ion Cells; Performance of AEA 80 Ah Battery Under GEO Profile; LEO Li-Ion Battery Testing; A Review of the Feasibility Investigation of Commercial Laminated Lithium-Ion Polymer Cells for Space Applications; Lithium-Ion Verification Test Program; Panasonic Small Cell Testing for AHPS; Lithium-Ion Small Cell Battery Shorting Study; Low-Earth-Orbit and Geosynchronous-Earth-Orbit Testing of 80 Ah Batteries under Real-Time Profiles; Update on Development of Lithium-Ion Cells for Space Applications at JAXA; Foreign Comparative Technology: Launch Vehicle Battery Cell Testing; 20V, 40 Ah Lithium Ion Polymer

76 FR 70531 - Fifth Meeting: RTCA Special Committee 225, Rechargeable Lithium Battery and Battery Systems-Small...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-14

... 225, Rechargeable Lithium Battery and Battery Systems--Small and Medium Size AGENCY: Federal Aviation..., Rechargeable Lithium Battery and Battery Systems--Small and Medium Size. SUMMARY: The FAA is issuing this notice to advise the public of a meeting of RTCA Special Committee 225, Rechargeable Lithium Battery and...

Second Life for Electric Vehicle Batteries: Answering Questions on Battery Degradation and Value

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neubauer, J. S.; Wood, E.; Pesaran, A.

2015-05-04

Battery second use – putting used plug-in electric vehicle (PEV) batteries into secondary service following their automotive tenure – has been proposed as a means to decrease the cost of PEVs while providing low cost energy storage to other fields (e.g. electric utility markets). To understand the value of used automotive batteries, however, we must first answer several key questions related to National Renewable Energy Laboratory (NREL) has developed a methodology and the requisite tools to answer these questions, including NREL’s Battery Lifetime Simulation Tool (BLAST). Herein we introduce these methods and tools, and demonstrate their application. We have foundmore » that capacity fade from automotive use has a much larger impact on second use value than resistance growth. Where capacity loss is driven by calendar effects more than cycling effects, average battery temperature during automotive service – which is often driven by climate – is found to be the single factor with the largest effect on remaining value. Installing hardware and software capabilities onboard the vehicle that can both infer remaining battery capacity from in-situ measurements, as well as track average battery temperature over time, will thereby facilitate the second use of automotive batteries.« less

Progress in battery technology since the First CSULB Annual Battery Conference and prospects for the future

NASA Astrophysics Data System (ADS)

Pickett, David F., Jr.

1992-04-01

An evaluation is made of noteworthy trends in the development of advanced electrochemical cells since January 1986. The advancements noted encompass LiAr batteries, spacecraft power supply Ni-H and Li-SO2 batteries, battery-powered biomedical devices, rechargeable Li-ion batteries, and the development of ambient temperature rechargeable lithium polymer solid electrolyte batteries. Attention is given to OSHA regulatory guidelines for recently commercially introduced advanced battery systems.

Immuno-detection of dioxins using a recombinant protein of aryl hydrocarbon receptor (AhR) fused with sfGFP.

PubMed

Faiad, Walaa; Hanano, Abdulsamie; Kabakibi, Mohamed Maher; Abbady, Abdul Qader

2016-06-21

Dioxins are one of the most toxic groups of persistent organic pollutants. Their bioaccumulation through the food chain constitutes a potential risk for human health. Upon cell entry, dioxins bind specifically and firmly to the aryl hydrocarbon receptor (AhR), leading to the stimulation of several enzymes responsible for its detoxification. Dioxin/AhR interaction could be exploited as an affordable alternative to a variety of analytical methods for detecting dioxin contamination in the environment. In this work, the ligand binding domain (LBD) of the AhR was cloned downstream a superfolder form of the green fluorescent protein (sfGFP), resulting in the construct pRSET-sfGFP-AhR. High level of expressed sfGFP-AhR fusion protein (50 kDa) was recovered from the inclusion bodies of E. coli by simple solubilization with the Arginine, and purified by affinity chromatography via its N-terminal 6 × His tag. Its purity was confirmed by SDS-PAGE analysis and immunoblotting with anti-His or anti-GFP antibodies. Indirect ELISA revealed the ability of the sfGFP-AhR, but not the sfGFP, to bind to the immobilized dioxin with the possibility to detect such interaction by both its 6 × His and GFP tags,Competitive ELISA showed that anti-dioxin antibody was more sensitive to low dioxin concentrations than sfGFP-AhR. Nevertheless,the detection range of sfGFP-AhR fusion was much wider and the detection limit was of about 10 ppt (parts per trillion) of free dioxin in the tested artificial samples. this highly expressed and functional sfGFP-AhR fusion protein provides a promising molecular tool for detecting and quantifying different congeners of dioxins.

Sodium sulfur battery seal

DOEpatents

Topouzian, Armenag

1980-01-01

This invention is directed to a seal for a sodium sulfur battery in which a flexible diaphragm sealing elements respectively engage opposite sides of a ceramic component of the battery which separates an anode compartment from a cathode compartment of the battery.

Sea water rope batteries

NASA Astrophysics Data System (ADS)

Walsh, M.

1984-05-01

This research demonstrated the feasibility of supplying approximately 1 watt of electrical power for one year on the sea bed with a novel battery, the rope battery. The proposed battery would look very much like a small diameter wire rope, possibly hundreds of feet long. This unusual shape permits the rope battery to take full advantage of the vastness of the ocean floor and permits at great pressure the steady diffusion of reaction products away from the battery itself. A sea water battery is described consisting of an inner bundle of coated wires which slowly corrode and an outer layer of fine wires which simultaneously provides strength, armor and surface area for slow hydrogen evolution. Two variations are examined. The fuse utilizes magnesium wires and burns slowly from the end. The rope utilizes lithium-zinc alloys and is slowly consumed along its entire length.

Development of battery management system for nickel-metal hydride batteries in electric vehicle applications

NASA Astrophysics Data System (ADS)

Jung, Do Yang; Lee, Baek Haeng; Kim, Sun Wook

Electric vehicle (EV) performance is very dependent on traction batteries. For developing electric vehicles with high performance and good reliability, the traction batteries have to be managed to obtain maximum performance under various operating conditions. Enhancement of battery performance can be accomplished by implementing a battery management system (BMS) that plays an important role in optimizing the control mechanism of charge and discharge of the batteries as well as monitoring the battery status. In this study, a BMS has been developed for maximizing the use of Ni-MH batteries in electric vehicles. This system performs several tasks: the control of charging and discharging, overcharge and over-discharge protection, the calculation and display of state-of-charge (SOC), safety, and thermal management. The BMS is installed in and tested in a DEV5-5 electric vehicle developed by Daewoo Motor Co. and the Institute for Advanced Engineering in Korea. Eighteen modules of a Panasonic nickel-metal hydride (Ni-MH) battery, 12 V, 95 A h, are used in the DEV5-5. High accuracy within a range of 3% and good reliability are obtained. The BMS can also improve the performance and cycle-life of the Ni-MH battery peak, as well as the reliability and the safety of the electric vehicles.

Aryl hydrocarbon receptor (AhR)-dependent regulation of pulmonary miRNA by chronic cigarette smoke exposure.

PubMed

Rogers, Sarah; de Souza, Angela Rico; Zago, Michela; Iu, Matthew; Guerrina, Necola; Gomez, Alvin; Matthews, Jason; Baglole, Carolyn J

2017-01-12

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically known for its toxic responses to man-made pollutants such as dioxin. More recently, the AhR has emerged as a suppressor of inflammation, oxidative stress and apoptosis from cigarette smoke by mechanisms that may involve the regulation of microRNA. However, little is known about the AhR regulation of miRNA expression in the lung in response to inhaled toxicants. Therefore, we exposed Ahr -/- and Ahr +/- mice to cigarette smoke for 4 weeks and evaluated lung miRNA expression by PCR array. There was a dramatic regulation of lung miRNA by the AhR in the absence of exogenous ligand. In response to cigarette smoke, there were more up-regulated miRNA in Ahr -/- mice compared to Ahr +/- mice, including the cancer-associated miRNA miR-96. There was no significant change in the expression of the AhR regulated proteins HuR and cyclooxygenase-2 (COX-2). There were significant increases in the anti-oxidant gene sulfiredoxin 1 (Srxn1) and FOXO3a- predicted targets of miR-96. Collectively, these data support a prominent role for the AhR in regulating lung miRNA expression. Further studies to elucidate a role for these miRNA may further uncover novel biological function for the AhR in respiratory health and disease.

In vitro bioanalysis of drinking water from source to tap.

PubMed

Rosenmai, Anna Kjerstine; Lundqvist, Johan; le Godec, Théo; Ohlsson, Åsa; Tröger, Rikard; Hellman, Björn; Oskarsson, Agneta

2018-08-01

The presence of chemical pollutants in sources of drinking water is a key environmental problem threatening public health. Efficient removal of pollutants in drinking water treatment plants (DWTPs) is needed as well as methods for assessment of the total impact of all present chemicals on water quality. In the present study we have analyzed the bioactivity of water samples from source to tap, including effects of various water treatments in a DWTP, using a battery of cell-based bioassays, covering health-relevant endpoints. Reporter gene assays were used to analyze receptor activity of the aryl hydrocarbon receptor (AhR), estrogen receptor (ER), androgen receptor (AR), peroxisome proliferator-activated receptor alpha (PPARα) and induction of oxidative stress by the nuclear factor erythroid 2-related factor 2 (Nrf2). DNA damage was determined by Comet assay. Grab water samples were concentrated by HLB or ENV solid phase extraction and the water samples assayed at a relative enrichment factor of 50. The enrichment procedure did not induce any bioactivity. No bioactivity was detected in Milli-Q water or drinking water control samples. Induction of AhR, ER and Nrf2 activities was revealed in source to tap water samples. No cytotoxicity, PPARα or AR antagonist activity, or DNA damage were observed in any of the water samples. A low AR agonist activity was detected in a few samples of surface water, but not in the samples from the DWTP. The treatment steps at the DWTP, coagulation, granulated activated carbon filtration, UV disinfection and NH 2 Cl dosing had little or no effect on the AhR, Nrf2 and ER bioactivity. However, nanofiltration and passage through the distribution network drastically decreased AhR activity, while the effect on Nrf2 activity was more modest and no apparent effect was observed on ER activity. The present results suggest that bioassays are useful tools for evaluation of the efficiency of different treatment steps in DWTPs in reducing toxic

Battery Technology Stores Clean Energy

NASA Technical Reports Server (NTRS)

2008-01-01

Headquartered in Fremont, California, Deeya Energy Inc. is now bringing its flow batteries to commercial customers around the world after working with former Marshall Space Flight Center scientist, Lawrence Thaller. Deeya's liquid-cell batteries have higher power capability than Thaller's original design, are less expensive than lead-acid batteries, are a clean energy alternative, and are 10 to 20 times less expensive than nickel-metal hydride batteries, lithium-ion batteries, and fuel cell options.

An introduction to lithium batteries

NASA Astrophysics Data System (ADS)

Garrard, W. N. C.

1988-09-01

Lithium batteries are being introduced into all three services in the Australian Defence Force. However, general information concerning lithium batteries is not available in a condensed form. This review examines various aspects of lithium batteries, including battery technology, safety aspects, purchasing, packaging, transport, storage and disposal.

Electric Vehicle Battery Challenge

ERIC Educational Resources Information Center

Roman, Harry T.

2014-01-01

A serious drawback to electric vehicles [batteries only] is the idle time needed to recharge their batteries. In this challenge, students can develop ideas and concepts for battery change-out at automotive service stations. Such a capability would extend the range of electric vehicles.

An averaging battery model for a lead-acid battery operating in an electric car

NASA Technical Reports Server (NTRS)

Bozek, J. M.

1979-01-01

A battery model is developed based on time averaging the current or power, and is shown to be an effective means of predicting the performance of a lead acid battery. The effectiveness of this battery model was tested on battery discharge profiles expected during the operation of an electric vehicle following the various SAE J227a driving schedules. The averaging model predicts the performance of a battery that is periodically charged (regenerated) if the regeneration energy is assumed to be converted to retrievable electrochemical energy on a one-to-one basis.

The Extravehicular Maneuvering Unit's New Long Life Battery and Lithium Ion Battery Charger

NASA Technical Reports Server (NTRS)

Russell, Samuel P.; Elder, Mark A.; Williams, Anthony G.; Dembeck, Jacob

2010-01-01

The Long Life (Lithium Ion) Battery is designed to replace the current Extravehicular Mobility Unit Silver/Zinc Increased Capacity Battery, which is used to provide power to the Primary Life Support Subsystem during Extravehicular Activities. The Charger is designed to charge, discharge, and condition the battery either in a charger-strapped configuration or in a suit-mounted configuration. This paper will provide an overview of the capabilities and systems engineering development approach for both the battery and the charger

Towards Resolving the Pro- and Anti-Tumor Effects of the Aryl Hydrocarbon Receptor.

PubMed

Narasimhan, Supraja; Stanford Zulick, Elizabeth; Novikov, Olga; Parks, Ashley J; Schlezinger, Jennifer J; Wang, Zhongyan; Laroche, Fabrice; Feng, Hui; Mulas, Francesca; Monti, Stefano; Sherr, David H

2018-05-07

We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages of some cancers when chronically activated by endogenous ligands. However, other studies have suggested that, under some circumstances, the AHR can oppose tumor aggression. Resolving this apparent contradiction is critical to the design of AHR-targeted cancer therapeutics. Molecular (siRNA, shRNA, AHR repressor, CRISPR-Cas9) and pharmacological (AHR inhibitors) approaches were used to confirm the hypothesis that AHR inhibition reduces human cancer cell invasion (irregular colony growth in 3D Matrigel cultures and Boyden chambers), migration (scratch wound assay) and metastasis (human cancer cell xenografts in zebrafish). Furthermore, these assays were used for a head-to-head comparison between AHR antagonists and agonists. AHR inhibition or knockdown/knockout consistently reduced human ER − /PR − /Her2 − and inflammatory breast cancer cell invasion, migration, and metastasis. This was associated with a decrease in invasion-associated genes (e.g., Fibronectin , VCAM1 , Thrombospondin, MMP1 ) and an increase in CDH1/E-cadherin , previously associated with decreased tumor aggression. Paradoxically, AHR agonists (2,3,7,8-tetrachlorodibenzo- p -dioxin and/or 3,3′-diindolylmethane) similarly inhibited irregular colony formation in Matrigel and blocked metastasis in vivo but accelerated migration. These data demonstrate the complexity of modulating AHR activity in cancer while suggesting that AHR inhibitors, and, under some circumstances, AHR agonists, may be useful as cancer therapeutics.

Batteries: An Advanced Na-FeCl2 ZEBRA Battery for Stationary Energy Storage Application

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Guosheng; Lu, Xiaochuan; Kim, Jin Yong

2015-06-17

Sodium-metal chloride batteries, ZEBRA, are considered as one of the most important electrochemical devices for stationary energy storage applications because of its advantages of good cycle life, safety, and reliability. However, sodium-nickel chloride (Na-NiCl2) batteries, the most promising redox chemistry in ZEBRA batteries, still face great challenges for the practical application due to its inevitable feature of using Ni cathode (high materials cost). In this work, a novel intermediate-temperature sodium-iron chloride (Na-FeCl2) battery using a molten sodium anode and Fe cathode is proposed and demonstrated. The first use of unique sulfur-based additives in Fe cathode enables Na-FeCl2 batteries can bemore » assembled in the discharged state and operated at intermediate-temperature (<200°C). The results in this work demonstrate that intermediate-temperature Na-FeCl2 battery technology could be a propitious solution for ZEBRA battery technologies by replacing the traditional Na-NiCl2 chemistry.« less

Polyoxometalate flow battery

DOEpatents

Anderson, Travis M.; Pratt, Harry D.

2016-03-15

Flow batteries including an electrolyte of a polyoxometalate material are disclosed herein. In a general embodiment, the flow battery includes an electrochemical cell including an anode portion, a cathode portion and a separator disposed between the anode portion and the cathode portion. Each of the anode portion and the cathode portion comprises a polyoxometalate material. The flow battery further includes an anode electrode disposed in the anode portion and a cathode electrode disposed in the cathode portion.

Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult

PubMed Central

Carreira, Vinicius S.; Fan, Yunxia; Kurita, Hisaka; Wang, Qin; Ko, Chia-I; Naticchioni, Mindi; Jiang, Min; Koch, Sheryl; Zhang, Xiang; Biesiada, Jacek; Medvedovic, Mario; Xia, Ying; Rubinstein, Jack; Puga, Alvaro

2015-01-01

The Developmental Origins of Health and Disease (DOHaD) Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr -/- and in utero TCDD-exposed Ahr +/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr -/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease. PMID:26555816

Development status of a sealed bipolar lead/acid battery for high-power battery applications

NASA Astrophysics Data System (ADS)

Arias, J. L.; Rowlette, J. J.; Drake, E. D.

A sealed bipolar lead/acid (SBLA) battery is being developed by Arias Research Associates (ARA) which will offer a number of important advantages in applications requiring high power densities. These applications include electric vehicles (EVs) and hybrid electric vehicles, uninterruptable power supplies (UPS), electrically-heated catalysts (EHCs) for automobiles, utility-power peak-shaving, and others. The advantages of the SBLA over other types of batteries will by significantly higher power density, together with good energy density, high cycle life, high voltage density, low production cost and zero maintenance. In addition, the lead/acid battery represents a technology which is familiar and accepted by Society, is recyclable within the existing infrastructure, and does not raise the safety concerns of many other new batteries (e.g., fire, explosion and toxic gases). This paper briefly reviews the basic design concepts and issues of the SBLA battery technology, various quasi-bipolar approaches and the results of ARA's development work during the past four years. Performance data are given based on both in-house and independent testing of ARA laboratory test batteries. In addition, performance projections and other characteristics are given for three ARA SBLA battery designs, which are compared with other batteries in three example applications: UPS, EHCs, and EVs. The most notable advantages of the SBLA battery are substantial reductions in product size and weight for the UPS, smaller packaging and longer life for the EHC, and higher vehicle performance and lower cost for the EV, compared to both existing and advanced EV batteries.

A battery simulator

NASA Technical Reports Server (NTRS)

Ferrell, S., Jr.; Lahr, N.

1970-01-01

Simulator verifies proper operation of a battery cell voltage-monitoring device. It also contains variable ac voltage to ascertain that a battery scanner will perform its function at all possible ac voltages.

49 CFR 173.159 - Batteries, wet.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 2 2010-10-01 2010-10-01 false Batteries, wet. 173.159 Section 173.159... Batteries, wet. (a) Electric storage batteries, containing electrolyte acid or alkaline corrosive battery fluid (wet batteries), may not be packed with other materials except as provided in paragraphs (g) and...

49 CFR 173.159 - Batteries, wet.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 2 2014-10-01 2014-10-01 false Batteries, wet. 173.159 Section 173.159... Batteries, wet. (a) Electric storage batteries, containing electrolyte acid or alkaline corrosive battery fluid (wet batteries), may not be packed with other materials except as provided in paragraphs (g) and...

49 CFR 173.159 - Batteries, wet.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 2 2012-10-01 2012-10-01 false Batteries, wet. 173.159 Section 173.159... Batteries, wet. (a) Electric storage batteries, containing electrolyte acid or alkaline corrosive battery fluid (wet batteries), may not be packed with other materials except as provided in paragraphs (g) and...

49 CFR 173.159 - Batteries, wet.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 2 2013-10-01 2013-10-01 false Batteries, wet. 173.159 Section 173.159... Batteries, wet. (a) Electric storage batteries, containing electrolyte acid or alkaline corrosive battery fluid (wet batteries), may not be packed with other materials except as provided in paragraphs (g) and...

49 CFR 173.159 - Batteries, wet.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 2 2011-10-01 2011-10-01 false Batteries, wet. 173.159 Section 173.159... Batteries, wet. (a) Electric storage batteries, containing electrolyte acid or alkaline corrosive battery fluid (wet batteries), may not be packed with other materials except as provided in paragraphs (g) and...

Battery-Charge-State Model

NASA Technical Reports Server (NTRS)

Vivian, H. C.

1985-01-01

Charge-state model for lead/acid batteries proposed as part of effort to make equivalent of fuel gage for battery-powered vehicles. Models based on equations that approximate observable characteristics of battery electrochemistry. Uses linear equations, easier to simulate on computer, and gives smooth transitions between charge, discharge, and recuperation.

Indoor air pollution and neural tube defects: effect modification by maternal genes.

PubMed