Hokkaido Institute of Public Health

Kita-ku, Japan

Hokkaido Institute of Public Health

Kita-ku, Japan
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Takeuchi S.,Hokkaido Institute of Public Health | Anezaki K.,Japan Institute for Environmental Sciences | Kojima H.,Hokkaido Institute of Public Health
Environmental Pollution | Year: 2017

In recent years, some pigments and chemical products have been reported to contain polychlorinated biphenyl (PCB) congeners as unintentional byproducts, and these have also been detected in residential environments from indoor air and house dust. In this study, using in vitro reporter gene assays, we characterized the agonistic and antagonistic activities of a total of 25 PCB congeners contained in pigments (PCB-1 to -16, -20, -35, -40, -52, -56, -77, -101, -126, and -153) against five nuclear hormone receptors, (estrogen receptor (ER) α/β, glucocorticoid receptor (GR), androgen receptor (AR), thyroid hormone receptor (TR) α1) and aryl hydrocarbon receptor (AhR). In the ERα/β assays, 19 and 13 of the 25 PCBs tested showed ERα/β agonistic and/or antagonistic activities, respectively. Relatively potent agonistic activities against ERα/β were found in PCB congeners possessing chlorides at positions 2 and 3. In the GR and AR assays, five and all of the 25 PCB congeners showed antagonistic activity, respectively. Among the anti-androgenic PCB congeners, the activities were more potent in PCB congeners possessing more than three chlorides including consecutive ortho- and meta- or meta- and para-chlorides. In the AhR assay using a sensitive DR-EcoScreen cell line, five of the 25 PCB congeners showed agonistic activity. We newly found that PCB-1, -35 and -56 can act as AhR agonists. Despite these activities among the PCBs, the effects of PCB-11, mainly detected in pigments and chemical products, against these receptors were found to be weaker than those of other tested PCBs. These results suggest that unintentional PCBs in pigments and chemical products might act as agonists and/or antagonists against ERα/β, AR, GR, and AhR, and some of the PCBs might disrupt endocrine functions via multiple receptors and/or simultaneously induce dioxin-like activity via AhR. © 2017 Elsevier Ltd

Kojima H.,Hokkaido Institute of Public Health | Muromoto R.,Hokkaido University | Takahashi M.,Hokkaido University | Takeuchi S.,Hokkaido Institute of Public Health | And 3 more authors.
Toxicology and Applied Pharmacology | Year: 2012

The retinoic acid receptor-related orphan receptors α and γ (RORα and RORγ), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. However, it remains unclear whether environmental chemicals, including pesticides, have agonistic and/or antagonistic activity against RORα/γ. In this study, we investigated the RORα/γ activity of several azole-type fungicides, and the effects of these fungicides on the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In the ROR-reporter gene assays, five azole-type fungicides (imibenconazole, triflumizole, hexaconazole, tetraconazole and imazalil) suppressed RORα- and/or RORγ-mediated transcriptional activity as did benzenesulphonamide T0901317, a ROR inverse agonist and a liver X receptor (LXR) agonist. In particular, imibenconazole, triflumizole and hexaconazole showed RORγ inverse agonistic activity at concentrations of 10 -6M. However, unlike T0901317, these fungicides failed to show any LXRα/β agonistic activity. Next, five azole-type fungicides, showing ROR inverse agonist activity, were tested on IL-17 mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin. The quantitative RT-PCR analysis revealed that these fungicides suppressed the expression of IL-17 mRNA without effecting RORα and RORγ mRNA levels. In addition, the inhibitory effect of imibenconazole as well as that of T0901317 was absorbed in RORα/γ-knocked down EL4 cells. Taken together, these results suggest that some azole-type fungicides inhibit IL-17 production via RORα/γ. This also provides the first evidence that environmental chemicals can act as modulators of IL-17 expression in immune cells. © 2012 Elsevier Inc..

Takeuchi S.,Hokkaido Institute of Public Health | Shiraishi F.,Japan National Institute of Environmental Studies | Kitamura S.,Nihon Pharmaceutical University | Kuroki H.,Tamagawa University | And 2 more authors.
Toxicology | Year: 2011

Hydroxylated polychlorinated biphenyls (OH-PCBs), major metabolites of PCBs, have been reported to act as estrogen receptor α (ERα) agonists or antagonists. However, little concern has been paid to the ability of OH-PCBs to interfere with other steroid hormone receptors such as ERβ, androgen receptor (AR) or glucocorticoid receptor (GR). In this study, we characterized the agonistic and antagonistic activities of available 100 OH-PCBs (39 ortho-, 24 meta-, and 37 para-OH compounds), including some congeners identified in humans, against human ERα/β, AR, and GR using in vitro reporter gene assays. In the ERα assay, 45 and 9 of the 100 OH-PCBs tested showed agonistic and antagonistic activities, respectively. In the ERβ assay, 45 and 6 compounds showed agonistic and antagonistic activities, respectively. In the AR and GR assays, although none of the compounds tested showed agonistic activity, 83 and 30 of the 100 OH-PCBs showed antagonistic activity, respectively. These AR and/or GR antagonistic compounds had various patterns of substituent in the structure, while relatively potent ERα/β agonistic and antagonistic compounds possessed para- and ortho-OH structures, respectively. Three OH-PCBs, predominantly identified in human tissues, showed little ERα/β or AR activities, apart from the weak ERα and/or GR antagonistic activity observed in 4-OH-CB107 and 4-OH-CB187. Taken together, these results suggest that a large number of OH-PCBs might act as agonists and/or antagonists against ERα/β, AR and GR. © 2011 Elsevier Ireland Ltd.

Kojima H.,Hokkaido Institute of Public Health | Sata F.,Japan National Institute of Public Health | Takeuchi S.,Hokkaido Institute of Public Health | Sueyoshi T.,National Health Research Institute | Nagai T.,Hokkaido Institute of Public Health
Toxicology | Year: 2011

The nuclear receptor, pregnane X receptor (PXR), is a ligand-dependent transcription factor that regulates genes involved in xenobiotic metabolism. Recent studies have shown that PXR activation may affect energy metabolism as well as the endocrine and immune systems. In this study, we characterized and compared the agonistic activities of a variety of pesticides against human PXR (hPXR) and mouse PXR (mPXR). We tested the hPXR and mPXR agonistic activity of 200 pesticides (29 organochlorines, 11 diphenyl ethers, 56 organophosphorus pesticides, 12 pyrethroids, 22 carbamates, 12 acid amides, 7 triazines, 7 ureas, and 44 others) by reporter gene assays using COS-7 simian kidney cells. Of the 200 pesticides tested, 106 and 93 activated hPXR and mPXR, respectively, and a total of 111 had hPXR and/or mPXR agonistic activity with greater or lesser inter-species differences. Although all of the pyrethroids and most of the organochlorines and acid amides acted as PXR agonists, a wide range of pesticides with diverse structures also showed hPXR and/or mPXR agonistic activity. Among the 200 pesticides, pyributicarb, pretilachlor, piperophos and butamifos for hPXR, and phosalone, prochloraz, pendimethalin, and butamifos for mPXR, acted as particularly potent activators at low concentrations in the order of 10-8-10-7M. In addition, we found that several organophosphorus oxon- and pyributicarb oxon-metabolites decreased PXR activation potency compared to their parent compounds. These results suggest that a large number of structurally diverse pesticides and their metabolites possess PXR-mediated transcriptional activity, and their ability to do so varies in a species-dependent manner in humans and mice. © 2010 Elsevier Ireland Ltd.

Kojima H.,Hokkaido Institute of Public Health | Takeuchi S.,Hokkaido Institute of Public Health | Itoh T.,Asahikawa Medical College | Iida M.,Otsuka Pharmaceutical Factory Inc. | And 2 more authors.
Toxicology | Year: 2013

Various organophosphate flame retardants (OPFRs) are widely used in building materials, textiles and electric appliances, and have been reported to cause indoor environmental pollution in houses and office buildings. In this study, using cell-based transactivation assays, we characterized the agonistic and/or antagonistic activities of 11 OPFRs against human nuclear receptors; estrogen receptor α (ERα), ERβ, androgen receptor (AR), glucocorticoid receptor (GR), thyroid hormone receptor α1 (TRα1), TRβ1, retinoic acid receptor α (RARα), retinoid X receptor α (RXRα), pregnane X receptor (PXR), peroxisome proliferator-activated receptor α (PPARα), and PPARγ. Of the 11 OPFRs tested, triphenyl phosphate (TPhP) and tricrecyl phosphate (TCP) showed ERα and/or ERβ agonistic activity. In addition, tributyl phosphate (TBP), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), TPhP and TCP showed AR antagonistic activity, and TBP, tris(2-ethylhexyl) phosphate (TEHP), TDCPP, TPhP and TCP showed GR antagonistic activity. Furthermore, we found that seven compounds, TBP, tris(2-chloro-1-methylethyl) phosphate (TCPP), TEHP, tris(2-butoxyethyl) phosphate (TBEP), TDCPP, TPhP, and TCP, display PXR agonistic activity. However, none of test compounds showed agonistic or antagonistic activity against TRα/β, or agonistic activity against RARα, RXRα or PPARα/γ. Taken together, these results suggest that several OPFRs may have potential endocrine disrupting effects via ERα, ERβ, AR, GR and PXR. © 2013 Elsevier Ireland Ltd.

Sato K.,Japan National Institute of Infectious Diseases | Takano A.,Yamaguchi University | Konnai S.,Hokkaido University | Nakao M.,Asahikawa Medical College | And 6 more authors.
Emerging Infectious Diseases | Year: 2014

We confirmed infection of 2 patients with Borrelia miyamotoi in Japan by retrospective surveillance of Lyme disease patients and detection of B. miyamotoi DNA in serum samples. One patient also showed seroconversion for antibody against recombinant glycerophosphodiester phosphodiesterase of B. miyamotoi. Indigenous relapsing fever should be considered a health concern in Japan.

Kojima H.,Hokkaido Institute of Public Health | Takeuchi S.,Hokkaido Institute of Public Health | Nagai T.,Hokkaido Institute of Public Health
Journal of Health Science | Year: 2010

Nuclear receptors (NRs) and the aryl hydrocarbon receptor (AhR) form a ligand-dependent transcription factor that regulates the genes involved in key physiological functions such as cell growth and differentiation, development, homeostasis, and metabolism. These receptors are potential targets of endocrine-disrupting chemicals (EDCs). To date, many studies have shown that EDCs, such as plasticizers, pesticides, and dioxins, can function as ligands of NRs and AhR. In this review, we focus on recent studies showing that a variety of pesticides, intentionally released into the environment, have agonistic and/or antagonistic activity against NRs and AhR, and present our transactivation assay-based screening results for 200 pesticides against estrogen receptors (ERs), androgen receptor (AR), thyroid hormone receptors (TRs), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), and AhR. Our studies have shown that a number of pesticides possess, and PXR agonistic activity as well as AR antagonistic activity, whereas none of the pesticides affect the TRα1,TRβ1,and PPAR antagonistic activity. Although the activities of each of these compounds were weak compared to those of endogenous hormone or dioxins, the endocrine-disrupting potential of pesticides, particularly those which function against ERα/β, AR, and PXR, may reflect that of numerous environmental chemicals. © 2010 The Pharmaceutical Society of Japan.

Yamano K.,Hokkaido Institute of Public Health | Koizumi A.,Keio University | Takeda T.,Keio University | Kiuchi F.,Keio University | Hada N.,Keio University
Parasitology Research | Year: 2012

The larval stage of Echinococcus multilocularis causes alveolar echinococcosis in human. In serodiagnosis of alveolar echinococcosis, specific reactions have been noted not only against protein antigens but also carbohydrates. With regard to protein antigens, the recent development of recombinant antigens has contributed to an improvement in serodiagnostic examination. On the contrary, the preparation of carbohydrate antigen still depends on extraction from crude antigens, and isolation is usually accompanied with difficulty; consequently, it is rare to examine individual antigenicity of carbohydrates. However, parasitic helminths express various antigenic carbohydrates. In the case of Echinococcus granulosus, antigenic glycoproteins of the laminated layer have been reported. Furthermore, the laminated layer of E. multilocularis contains Em2 antigen which is a famous mucin-type glycoprotein and which seems to play an important role in metacestode survival mechanisms within the immunologically reacting host; nevertheless, the anomeric configurations and the individual antigenicity of Em2 O-glycans have not been confirmed so far. Under these circumstances, we introduced a chemical synthesis to get pure oligosaccharides in order to assess diagnostic performance. In our previous study, 11 oligosaccharides have already been prepared by stereocontrolled syntheses. Among them, three synthetic oligosaccharides showed antigenicity. Our aim is to investigate correct sequence and serodiagnostic potential of the dominant epitope of Em2. This study provided important diagnostic information: (1) the trisaccharide Galα1-4Galβ1-3GalNAc sequence is the dominant epitope of Em2 (sensitivity 95.0 %), (2) Trematoda expresses carbohydrates with the similar trisaccharide sequence, and (3) the terminal Galα1-4Gal sequence is a candidate for thewidely common epitope that accounts for the cross-reaction. © Springer-Verlag 2012.

Kojima H.,Hokkaido Institute of Public Health | Takeuchi S.,Hokkaido Institute of Public Health | Van den Eede N.,University of Antwerp | Covaci A.,University of Antwerp
Toxicology Letters | Year: 2016

Organophosphate flame retardants (OPFRs) have been used in a wide variety of applications and detected in several environmental matrices, including indoor air and dust. Continuous human exposure to these chemicals is of growing concern. In this study, the agonistic and/or antagonistic activities of 12 primary OPFR-metabolites against ten human nuclear receptors were examined using cell-based transcriptional assays, and compared to those of their parent compounds. As a result, 3-hydroxylphenyl diphenyl phosphate and 4-hydroxylphenyl diphenyl phosphate showed more potent estrogen receptor α (ERα) and ERβ agonistic activity than did their parent, triphenyl phosphate (TPHP). In addition, these hydroxylated TPHP-metabolites also showed ERβ antagonistic activity at higher concentrations and exhibited pregnane X receptor (PXR) agonistic activity as well as androgen receptor (AR) and glucocorticoid receptor (GR) antagonistic activities at similar levels to those of TPHP. Bis(2-butoxyethyl) 3'-hydroxy-2-butoxyethyl phosphate and 2-hydroxyethyl bis(2-butoxyethyl) phosphate act as PXR agonists at similar levels to their parent, tris(2-butoxyethyl) phosphate. On the other hand, seven diester OPFR-metabolites and 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate did not show any receptor activity. Taken together, these results suggest that hydroxylated TPHP-metabolites show increased estrogenicity compared to the parent compound, whereas the diester OPFR-metabolites may have limited nuclear receptor activity compared to their parent triester OPFRs. © 2016 Elsevier Ireland Ltd.

Okano M.,Hokkaido Institute of Public Health
Current Pediatric Reviews | Year: 2015

Chronic active Epstein-Barr virus infection (CAEBV) is characterized mainly by prolonged or intermittent fever, lymphadenopathy and hepatosplenomegaly without definite underlying diseases at the diagnosis. Patients with CAEBV also may have various life-threatening conditions including hematological, neurological, pulmonary, cardiac, digestive tract, ocular and/or dermal disorders. Additionally, during the course of illness, they often develop hematological malignancies such as T cell, NK cell or B cell lymphoproliferative disorder (LPD) and/or lymphoma. No causative pathogenetic mechanisms have been sufficiently clarified, and additionally no promising efficacious treatment was demonstrated except for the hematopoietic stem cell transplantation (HSCT) in cases who develop T cell or NK cell LPD or lymphoma. This minireview outlines the recent development for the comprehensive viewpoints of CAEBV mainly regarding to virological, immunological, pathological and therapeutical progresses. © 2015 Bentham Science Publishers.

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