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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.


Watanabe Y.,Hiroshima University | Watanabe Y.,Nihon Pharmaceutical University | Kojima H.,Hokkaido Institute of Public Health | Takeuchi S.,Hokkaido Institute of Public Health | And 5 more authors.
Toxicology and Applied Pharmacology | Year: 2015

Benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) is widely used as sunscreen for protection of human skin and hair from damage by ultraviolet (UV) radiation. In this study, we examined the metabolism of BP-3 by rat and human liver microsomes, and the estrogenic and anti-androgenic activities of the metabolites. When BP-3 was incubated with rat liver microsomes in the presence of NADPH, 2,4,5-trihydroxybenzophenone (2,4,5-triOH BP) and 3-hydroxylated BP-3 (3-OH BP-3) were newly identified as metabolites, together with previously detected metabolites 5-hydroxylated BP-3 (5-OH BP-3), a 4-desmethylated metabolite (2,4-diOH BP) and 2,3,4-trihydroxybenzophenone (2,3,4-triOH BP). In studies with recombinant rat cytochrome P450, 3-OH BP-3 and 2,4,5-triOH BP were mainly formed by CYP1A1. BP-3 was also metabolized by human liver microsomes and CYP isoforms. In estrogen reporter (ER) assays using estrogen-responsive CHO cells, 2,4-diOH BP exhibited stronger estrogenic activity, 2,3,4-triOH BP exhibited similar activity, and 5-OH BP-3, 2,4,5-triOH BP and 3-OH BP-3 showed lower activity as compared to BP-3. Structural requirements for activity were investigated in a series of 14 BP-3 derivatives. When BP-3 was incubated with liver microsomes from untreated rats or phenobarbital-, 3-methylcholanthrene-, or acetone-treated rats in the presence of NADPH, estrogenic activity was increased. However, liver microsomes from dexamethasone-treated rats showed decreased estrogenic activity due to formation of inactive 5-OH BP-3 and reduced formation of active 2,4-diOH BP. Anti-androgenic activity of BP-3 was decreased after incubation with liver microsomes. © 2014 Elsevier Inc.


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.


Watanabe Y.,Nihon Pharmaceutical University | Watanabe Y.,Hiroshima University | Kojima H.,Hokkaido Institute of Public Health | Takeuchi S.,Hokkaido Institute of Public Health | And 3 more authors.
Food and Chemical Toxicology | Year: 2013

The structure-activity relationships of parabens which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated. Fourteen of 17 parabens exhibited hERα and/or hERβ agonistic activity at concentrations of ≤1×10-5M, whereas none of the 17 parabens showed AR agonistic or antagonistic activity. Among 12 parabens with linear alkyl chains ranging in length from C1 to C12, heptylparaben (C7) and pentylparaben (C5) showed the most potent ERα and ERβ agonistic activity in the order of 10-7M and 10-8M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12. Most parabens showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that parabens are selective agonists for ERβ over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. © 2013 Elsevier Ltd.


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.


Mizukami C.,Hokkaido University | Spiliotis M.,University of Bern | Gottstein B.,University of Bern | Yagi K.,Hokkaido Institute of Public Health | And 2 more authors.
Parasitology International | Year: 2010

We investigated the potential of gene silencing in Echinococcus multilocularis protoscoleces using RNA interference (RNAi). For the introduction of siRNA, soaking and electroporation were first examined for their effects on the viability of protoscoleces and their efficacy for siRNA introduction. Consequently, electroporation using 100. V and 800. μF showed the optimal results. This electroporation procedure was then evaluated for its ability to induce RNAi in protoscoleces using siRNAs targeting the 14-3-3 and elp genes. It was found that the levels of 14-3-3 and elp mRNA in 14-3-3 siRNA- and elp siRNA-treated protoscoleces were reduced to 21.8 ± 2.6 and 35.5 ± 0.4% of those of the untreated control by day 3, respectively. Moreover, the target proteins significantly decreased in the siRNA-treated samples by day 15. In the analysis of viability, the untreated control, electroporation control, 14-3-3 siRNA-treated, and elp siRNA-treated samples displayed 98.4 ± 1.4, 83.0 ± 2.5, 58.0 ± 23.0, and 55.1 ± 14.6% viability, respectively, on day 15. In conclusion, we successfully demonstrated that RNAi mediated the knock-down of target gene expression in E. multilocularis protoscoleces at both the transcriptional and translational levels. © 2010 Elsevier Ireland Ltd.


Matsumoto J.,Hokkaido University | Matsumoto J.,Nihon University | Kouguchi H.,Hokkaido Institute of Public Health | Oku Y.,Hokkaido University | Yagi K.,Hokkaido Institute of Public Health
Parasitology International | Year: 2010

We investigated parasite establishment, subsequent larval development and antibody responses in gerbils, cotton rats and 4 inbred mouse strains until 16. weeks post inoculation (p.i.) with 200 eggs of Echinococcus multilocularis. The rate of parasite establishment in the liver determined at 4. weeks p.i. was highest in DBA/2, followed by AKR/N, C57BL/10 and C57BL/6 mice, whereas gerbils harboured few parasite foci. The accurate number of liver lesions in cotton rats could not be determined due to rapid growth and advanced multivesiculation of the parasite observed at 2. weeks p.i. The course of larval development was most advanced in DBA/2 mice with mature protoscolex formation at 16. weeks p.i., followed by AKR/N harbouring metacestodes with sparsely distributed immature protoscoleces. On the other hand, C57BL/6 and C57BL/10 mice had infertile metacestodes without any protoscolex formation. The parasite growth in mice was totally slower than those in gerbils and cotton rats. Specific IgG and IgM responses against 3 types of native crude antigens of larval E. multilocularis were evaluated using somatic extracts of and vesicle fluid of metacestode, and somatic extracts from purified protoscoleces. The 4 mouse strains demonstrated basically similar kinetics with apparent IgG and IgM increases at 9. weeks p.i. and thereafter, except C57BL/10, exhibited higher levels of IgM against crude antigens at some time point of infection. On the other hand, a follow-up determination of specific IgG and IgM levels against recombinant antigens from larval E. multilocularis revealed that each mouse strain showed different antibody-level kinetics. The findings in the present study demonstrate that the course of host-parasite interactions in primary alveolar echinococcosis, caused by larval E. multilocularis, clearly varies among intermediate host rodents with different genetic backgrounds. © 2010 Elsevier Ireland Ltd.

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