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Yum S.,Korea Ocean Research and Development Institute | Woo S.,Korea Ocean Research and Development Institute | Kagami Y.,Ecogenomics Inc. | Park H.-S.,Korea Research Institute of Bioscience and Biotechnology | Ryu J.-C.,Korea Institute of Science and Technology
Comparative Biochemistry and Physiology - C Toxicology and Pharmacology | Year: 2010

Differential gene expression profiling was performed with a cDNA microarray in the liver tissue of the medaka fish, Oryzias latipes, after exposure to Arochlor 1260, a polychlorinated biphenyl (PCB) mixture, which is used as a coolant and insulating fluid for transformers and capacitors and is classified as a persistent organic pollutant. Twenty-six differentially expressed candidate genes were identified. The expression of 12 genes was up-regulated and that of 14 genes was down-regulated. These genes are associated with the cytoskeleton, development, endocrine/reproduction, immunity, metabolism, nucleic acid/protein binding, and signal transduction, or are uncategorized. The transcription of molecular biomarkers known to be involved in endocrine disruption (e.g., vitellogenins, choriogenins, and estrogen receptor α) was highly up-regulated. The same tendencies in gene expression changes were observed with real-time quantitative PCR (qRT-PCR) analysis, which was conducted to examine 12 selected candidate genes. These genes could be used as molecular biomarkers for biological responses to toxic chemicals, especially endocrine disrupting and carcinogenic chemical contamination in aquatic environments. © 2009 Elsevier Inc. All rights reserved. Source


Mitsui T.,Yamanashi University | Ishida M.,Yamanashi University | Izawa M.,Yamanashi University | Kagami Y.,Ecogenomics Inc. | Arita J.,Yamanashi University
Molecular and Cellular Endocrinology | Year: 2011

In addition to their well-known stimulatory action, estrogens have an anti-proliferative effect. The present study was undertaken to investigate the mechanism by which 17β-estradiol (E2) inhibits insulin-like growth factor-1 (IGF-1)-induced proliferation in vitro in the rat pituitary lactotroph, a typical estrogen-responsive cell. E2 treatment of pituitary cells did not change levels of IGF-1-induced phosphorylation of proliferation-related protein kinases such as Erk1/2 and Akt. We performed global gene expression profiling by DNA microarray analysis and identified 177 genes regulated by E2 in the presence of IGF-1. These results were verified by quantitative real time PCR. The estrogen-regulated genes included several NFκB family related genes. As pharmacological inhibition of the NFκB pathway blocked IGF-1-induced lactotroph proliferation, we chose to investigate whether one NFκB pathway gene, Bcl3, was involved in the anti-proliferative action of E2. RNA interference-mediated knockdown of Bcl3 expression attenuated IGF-1-induced lactotroph proliferation. Even minimal induced overexpression of Bcl3 blocked the anti-proliferative action of E2. In contrast, Nfkb2, another E2-downregulated protein, required maximal overexpression to block the anti-proliferative action of E2. These results suggest that inhibition of Bcl3 expression is involved in the anti-proliferative action of estrogens in pituitary lactotrophs in culture. © 2011 Elsevier Ireland Ltd. Source


Miyakawa H.,Japan National Institute for Basic Biology | Toyota K.,Japan National Institute for Basic Biology | Toyota K.,Graduate University for Advanced Studies | Hirakawa I.,Japan National Institute for Basic Biology | And 11 more authors.
Nature Communications | Year: 2013

Juvenile hormone is an essential regulator of major developmental and life history events in arthropods. Most of the insects use juvenile hormone III as the innate juvenile hormone ligand. By contrast, crustaceans use methyl farnesoate. Despite this difference that is tied to their deep evolutionary divergence, the process of this ligand transition is unknown. Here we show that a single amino-acid substitution in the receptor Methoprene-tolerant has an important role during evolution of the arthropod juvenile hormone pathway. Microcrustacea Daphnia pulex and D. magna share a juvenile hormone signal transduction pathway with insects, involving Methoprene-tolerant and steroid receptor coactivator proteins that form a heterodimer in response to various juvenoids. Juvenile hormone-binding pockets of the orthologous genes differ by only two amino acids, yet a single substitution within Daphnia Met enhances the receptor's responsiveness to juvenile hormone III. These results indicate that this mutation within an ancestral insect lineage contributed to the evolution of a juvenile hormone III receptor system. © 2013 Macmillan Publishers Limited. All rights reserved. Source


Hirakawa I.,Yamaguchi University | Hirakawa I.,Japan National Institute for Basic Biology | Hirakawa I.,Ecogenomics Inc. | Miyagawa S.,Japan National Institute for Basic Biology | And 12 more authors.
Chemosphere | Year: 2012

The occurrence of oocytes in the testis (testis-ova) of several fish species is often associated with exposure of estrogenic chemicals. However, induction mechanisms of the testis-ova remain to be elucidated. To develop marker genes for detecting testis-ova in the testis, adult male medaka were exposed to nominal concentration of 100ngL -1 of 17α-ethinylestradiol (EE2) for 3-5weeks, and 800ng estradiol benzoate (EB) for 3weeks (experiment I), and a measured concentration of 20ngL -1 EE2 for 1-6weeks (experiment II). Histological analysis was performed for the testis, and microarray analyses were performed for the testis, liver and brain. Microarray analysis in the estrogen-exposed medaka liver showed vitellogenin and choriogenin as estrogen responsive genes. Testis-ova were induced in the testis after 4weeks of exposure to 100ngL -1 EE2, 3weeks of exposure to 800ngEB, and 6weeks of exposure to 20ngL -1 EE2. Microarray analysis of estrogen-exposed testes revealed up-regulation of genes related to zona pellucida (ZP) and the oocytes marker gene, 42Sp50. Using quantitative RT-PCR we confirmed that Zpc5 gene can be used as a marker for the detection of testis-ova in male medaka. © 2011 Elsevier Ltd. Source


Miyagawa S.,Japan National Institute for Basic Biology | Lange A.,University of Exeter | Hirakawa I.,Japan National Institute for Basic Biology | Hirakawa I.,Ecogenomics Inc. | And 14 more authors.
Environmental Science and Technology | Year: 2014

Exposure to estrogenic endocrine disrupting chemicals (EDCs) induces a range of adverse effects, notably on reproduction and reproductive development. These responses are mediated via estrogen receptors (ERs). Different species of fish may show differences in their responsiveness to environmental estrogens but there is very limited understanding on the underlying mechanisms accounting for these differences. We used custom developed in vitro ERα reporter gene assays for nine fish species to analyze the ligand- and species-specificity for 12 environmental estrogens. Transcriptonal activities mediated by estradiol-17β (E2) were similar to only a 3-fold difference in ERα sensitivity between species. Diethylstilbestrol was the most potent estrogen (∼10-fold that of E2) in transactivating the fish ERαs, whereas equilin was about 1 order of magnitude less potent in all species compared to E2. Responses of the different fish ERαs to weaker environmental estrogens varied, and for some considerably. Medaka, stickleback, bluegill and guppy showed higher sensitivities to nonylphenol, octylphenol, bisphenol A and the DDT-metabolites compared with cyprinid ERαs. Triclosan had little or no transactivation of the fish ERαs. By constructing ERα chimeras in which the AF-containing domains were swapped between various fish species with contrasting responsiveness and subsequent exposure to different environmental estrogens. Our in vitro data indicate that the LBD plays a significant role in accounting for ligand sensitivity of ERα in different species. The differences seen in responsiveness to different estrogenic chemicals between species indicate environmental risk assessment for estrogens cannot necessarily be predicted for all fish by simply examining receptor activation for a few model fish species. © 2014 American Chemical Society. Source

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