KINDAI UNIVERSITY


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KAGAWA Nao

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FacultyDepartment of Life Science / Graduate School of Science and Engineering Research
PositionAssociate Professor
Degree
Commentator Guidehttps://www.kindai.ac.jp/meikan/899-kagawa-nao.html
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Last Updated :2020/09/30

Education and Career

Education

  •  - 2001 , Hokkaido University
  •  - 1996 , Hokkaido University, School of Fisheries Sciences

Academic & Professional Experience

  •   2008 09 ,  - 2009 08 , Visiting scholar, Stanford University

Research Activities

Research Areas

  • Life sciences, Marine/Aquatic life sciences

Research Interests

  • fish behaviour and neuroendocrinology

Published Papers

  • Physiological changes in response to social isolation in male medaka fish, Airi Otsuka, Moeko Inahata, Yuki Shimomura, Nao Kagawa, Fisheries Science, Fisheries Science, Jun. 2020 , Refereed
  • Neurodevelopmental toxicity in the mouse neocortex following prenatal exposure to acetamiprid, Kagawa, N, T. Nagao, Journal of Applied Toxicology, Journal of Applied Toxicology, DOI: 10.1002/jat.3692, Jun. 2018 , Refereed
  • Motor activities of newborns prenatally exposed to low-dose bisphenol A in diverse mouse strains, Kagawa,N, M. Komada, T. Nagao, Fundam. Toxicol. Sci., Fundam. Toxicol. Sci., 2, 79 - 82, May 2015 , Refereed
  • Aluminium and cadmium inhibit vitellogenin and its mRNA induction by estradiol-17 β in the primary culture of hepatocytes in the rainbow trout Oncorhynchus mykiss, Un-Gi Hwang, Nao Kagawa, Yasuo Mugiya, General and Comparative Endocrinology, General and Comparative Endocrinology, 119(1), 69 - 76, 2000 , Refereed
    Summary:Effects of Al and Cd on vitellogenin (VTG) and VTG mRNA induction by estradiol-17 β (E2) were examined in primary hepatocyte cultures of rainbow trout. Hepatocytes were precultured for 2 days and then E2 (2 x 10-6 M) and Al (10-6-10-4 M) or Cd (10-9-10-6 M) were simultaneously added to the incubation medium. Hepatocytes were cultured for 5 more days. Media and hepatocytes were then analyzed by SDS-PAGE and Northern blotting for VTG and VTG mRNA, respectively. These metals had no appreciable effect on the viability of hepatocytes in culture. However, Al and Cd interfered with VTG production and VTG mRNA expression. Al reduced VTG production in a concentration-dependent way and a significant reduction occurred at Al concentrations greater than 5 x 10-5 M. VTG mRNA expression also decreased with a negative correlation with Al concentrations (r = -0.98). The inhibition of VTG production by Cd was not concentration-dependent. This metal markedly inhibited VTG production and VTG mRNA expression at 10-6 M. The Al-induced inhibition of VTG production was restored 7 days after Al removal, but the Cd-induced inhibition was not restored. These results suggest that Al and Cd inhibit VTG production at the transcriptional level to reduce VTG mRNA expression by different mechanisms. (C) 2000 Academic Press.
  • Postnatal di-2-ethylhexyl phthalate exposure affects hippocampal dentate gyrus morphogenesis., Munekazu Komada, Tetsuji Nagao, Nao Kagawa, Journal of applied toxicology : JAT, Journal of applied toxicology : JAT, Jul. 07 2020 , Refereed
    Summary:Di-2-ethylhexyl phthalate (DEHP) is the most commonly used phthalate for the production of flexible polyvinyl chloride. Recent studies in humans reported a widespread DEHP exposure, raising concerns in infants whose metabolic and excretory systems are immature. DEHP is a potential endocrine-disrupting chemical, but the effects of postnatal DEHP exposure on neuronal development are unclear. The dentate gyrus (DG) is critical in the consolidation of information from short- to long-term memory, as well as spatial learning. We evaluated neurodevelopmental toxicity due to neonatal DEHP exposure by assessing neurogenesis in the DG. Newborn mice were orally administered DEHP from postnatal day (PND) 12 to 25. We performed immunostaining using neuronal markers at different stages to assess whether DEHP exposure affects neurons at specific differentiation stages at PND 26 and PND 110. We found that in mice, postnatal DEHP exposure led to a decrease in the number of Type-1, -2a, -2b, and -3 neural progenitor cells, as well as granule cells in the hippocampal DG at PND 26. Further, the results showed that neural progenitor cell proliferation and differentiation were also reduced in the hippocampal DG of the DEHP-exposed mice. However, no effect on memory and learning was observed. Overall, our results suggest that neurodevelopmental toxicity due to postnatal DEHP exposure might affect postnatal DG morphogenesis.
  • The presence of a conspecific induces risk-taking behaviour and enlargement of somata size of dopaminergic neurons in the brain of male medaka fish., Airi Otsuka, Kenta Shimomura, Haruka Niwa, Nao Kagawa, Journal of fish biology, Journal of fish biology, 96(4), 1014 - 1023, Apr. 2020 , Refereed
    Summary:Boldness and risk-taking behaviours in animals are important traits to obtain advantages such as habitation, food resources, reproductive success and social dominance. Risk-taking behaviour is influenced by physiological and environmental conditions; however, whether individual fish become bolder by the presence of conspecifics remains unknown. In this study, a light-dark preference test was conducted using medaka fish (Oryzias latipes) with or without a neighbouring conspecific. It was found that individual medaka male fish preferred a light environment and avoided a dark environment, whereas the display of a neighbouring conspecific enhanced the time the male spent in the dark environment (i.e., this condition encouraged risk-taking). The blood glucose level increased in fish confined to the dark condition but did not increase in light-preferring fish and risk-taking fish. Large somata expressing tyrosine hydroxylase, which is the rate-limiting enzyme in dopamine synthesis, were detected in the telencephalic and diencephalic brain regions in risk-taking medaka, whereas large somata were detected in the diencephalic region in medaka confined to the dark condition. These findings indicated that medaka is a good fish model to explore the central roles of dopaminergic neurons in the telencephalon and the diencephalon, which regulate risk-taking behaviour.
  • Maternal administration of bisphenol A alters the microglial profile in the neocortex of mouse weanlings., Nao Kagawa, Tetsuji Nagao, Congenital anomalies, Congenital anomalies, Mar. 29 2020 , Refereed
    Summary:Bisphenol A (BPA) is known to cause abnormal neurogenesis in the developing neocortex. The mechanisms of BPA toxicity concerning neuroinflammatory-related endpoints are incompletely characterized. To evaluate the microglial morphology and the gene expression of pro-inflammatory cytokines in the newborn neocortex, ICR mice were exposed to BPA 200 μg/kg/d on gestational day 6 through post-partum day 21. Weanlings exposed during prenatal and postnatal period to BPA showed an increased number of amoeboid-type microglia, a microglial differentiation disruption (the M1/M2 microglial ratio), and an abnormal expression of genes encoding pro-inflammatory factors. These findings suggest that the well-known neurodevelopmental toxicity of BPA may be related to an increased microglial activation and neuroinflammation in the neocortex.
  • The neonicotinoids acetamiprid and imidacloprid impair neurogenesis and alter the microglial profile in the hippocampal dentate gyrus of mouse neonates., Akira Nakayama, Manami Yoshida, Nao Kagawa, Tetsuji Nagao, Journal of applied toxicology : JAT, Journal of applied toxicology : JAT, 39(6), 877 - 887, Jun. 2019 , Refereed
    Summary:Acetamiprid (ACE) and imidacloprid (IMI) are widely used neonicotinoid pesticides. They bind selectively to insect nicotinic acetylcholine receptors (nAChRs) and are considered non-hazardous to mammals. Few studies have assessed the activation of vertebrate nAChRs and the neurodevelopmental toxicity following in utero or neonatal exposure to neonicotinoids; therefore, we evaluated the effects of ACE or IMI exposure on neurogenesis and microglial profiles in the developing hippocampal dentate gyrus (DG) of mouse neonates. Mice were exposed to ACE, IMI (both 5 mg/kg/day) or nicotine (0.5 mg/kg/day) from postnatal day (P)12 to P26 by oral gavage. On P27, brains were removed, and neurogenesis and microglial activation in the hippocampal DG were examined via immunohistochemistry. A reduction in neurogenesis in the hippocampal DG of neonates following ACE, IMI and nicotine treatment was found. Additionally, neonicotinoid-exposed newborns showed an increase in the number of amoeboid-type and activated M1-type microglia. These results suggest that exposure to ACE and IMI impairs neurogenesis and alters microglial profiles in the developing hippocampal DG following oral dosing in an early postnatal period. A better understanding of the potential effects of these pesticides on human infant health is an important goal of our research.
  • Reduction of Tryptophan Hydroxylase Expression in the Brain of Medaka Fish After Repeated Heat Stress., Yuki Shimomura, Moeko Inahata, Mai Komori, Nao Kagawa, Zoological science, Zoological science, 36(3), 223 - 230, Jun. 01 2019 , Refereed
    Summary:Serotonin (i.e., 5-hydroxytryptamine [5-HT]) plays a key role in stress responses in vertebrates. In mammals and teleosts, tryptophan hydroxylase (Tph), a rate-limiting enzyme in the biosynthesis of 5-HT, includes two paralogs: Tph 1 and Tph 2. The response of the Tphs to stress has been reported in mammals, but less is known about the responses of these enzymes to stress in fish. In the present study, we examined whether heat stress affects the mRNA expression of these Tphs in the brain of medaka fish (Oryzias latipes). We also determined the concentration of 5-HT in the brain, the mRNA expression of heat shock protein 90 alpha (Hsp90α) in the liver, plasma cortisol concentration, and blood glucose concentration in medaka. Whole-body exposure to repeated heat stress significantly decreased the mRNA expression of Tph1 and Tph2 in male and female medaka, whereas single heat stress did not affect the expression of either of the mRNAs. The 5-HT concentration also decreased significantly after repeated heat stress sessions in both sexes, but did not decrease after a single heat stress session. After single and repeated heat stress sessions, Hsp90α mRNA expression increased in both sexes; however, increments in the concentrations of plasma cortisol and blood glucose occurred in male, but not in female, medaka. These results suggest that both types of Tphs are involved in reducing 5-HT in the brain and are reliable indicators of chronic stress response in both sexes. However, stress responses in plasma cortisol and blood glucose concentrations differ between male and female medaka.
  • Social rank-dependent expression of gonadotropin-releasing hormones and kisspeptin in the medaka brain, Nao Kagawa, Sayuri Hirose, Keiko Fujimoto, Chihomi Nomura, Yuuma Fujita, Akira Honda, Mai Komori, GENERAL AND COMPARATIVE ENDOCRINOLOGY, GENERAL AND COMPARATIVE ENDOCRINOLOGY, 249, 48 - 54, Aug. 2017 , Refereed
    Summary:Social interactions regulate the expression of several neuropeptides that have a central role in the reproductive system of mammals. Nonmammalian vertebrates also have these neuropeptides or paralogs, however, studies on the social regulation of reproductive physiology in nonmammalian species are limited. In this study, we examined whether the expression of gonadotropin-releasing hormones (GnRHs) and kisspeptin (Kiss1) is affected by social hierarchy resulting from the outcomes of male-male competition in medaka fish (Oryzias latipes). Four males were introduced to each other in an experimental tank, and classified as the most aggressive dominant or the most submissive subordinate fish, based on the frequency of their aggressive acts during a short-term competition. Dominant and subordinate males maintained their social rank during a long-term competition. Immediately after short-term competition, gonadotropin-releasing hormone-3 (GnRH3) level in the olfactory bulb was significantly higher in subordinate males than in dominant males. After long-term competition, dominant males had high level of gonadotropin-releasing hormone-1 (GnRH1) in the preoptic area, whereas subordinate males had lower Kissl level in the nucleus ventral tuberis. On the other hand, the levels of gonadotropin-releasing hormone-2 (GnRH2) in the nucleus lateralis valvulae and Kissl in the nucleus posterioris periventricularis, and plasma 11-ketotestosterone (11-KT) concentration did not differ between subordinate and dominant males after the short- and long-term competitions. These results suggest that social hierarchy regulates the expression of GnRH1, GnRH3, and Kissl without affecting 11-KT level in male medaka. (C) 2017 Elsevier Inc. All rights reserved.
  • Mechanisms underlying neuro-inflammation and neurodevelopmental toxicity in the mouse neocortex following prenatal exposure to ethanol, Munekazu Komada, Nao Hara, Satoko Kawachi, Kota Kawachi, Nao Kagawa, Tetsuji Nagao, Yayoi Ikeda, SCIENTIFIC REPORTS, SCIENTIFIC REPORTS, 7, Jul. 2017 , Refereed
    Summary:Fetal alcohol spectrum disorders (FASD) constitute a wide range of disorders that arise from prenatal exposure to ethanol (EtOH). However, detailed reports regarding the adverse effects of prenatal EtOH exposure on neocortical morphology and its underlying pathogenic mechanisms are limited. In the present study, we aimed to characterize the anatomical abnormalities of neocortical development and their correlation with microglial properties and neuro-inflammation in a mouse model of FASD. We evaluated the development and maturation of the neocortex in ICR mice prenatally exposed to 25% (w/v) EtOH using histological and molecular analyses. Reduced proliferation and excessive cell death were observed in the dorsal telencephalon. Abnormal neuronal distribution, layer formation, and dopaminergic neuronal projections were observed in the neocortex. Disruption of microglial differentiation (M-1/M-2 microglial ratio) and abnormal expression of pro-inflammatory and neurotrophic factors were induced, and these abnormalities were ameliorated by co-treatment with an antiinflammatory drug (pioglitazone). FASD model mice displayed histological abnormalities, microglial abnormalities, and neuro-inflammation in both the embryonic and newborn stages. Thus, antiinflammatory therapeutics may provide a novel preventive approach for the treatment of FASD.
  • Prenatal exposure to di(2-ethylhexyl) phthalate impairs development of the mouse neocortex, Munekazu Komada, Yuuya Gendai, Nao Kagawa, Tetsuji Nagao, Toxicology Letters, Toxicology Letters, 259, 69 - 79, Sep. 30 2016 , Refereed
    Summary:Di(2-ethylhexyl) phthalate (DEHP) is currently the most commonly used phthalate for the production of flexible polyvinyl chloride. Phthalates including DEHP have been labeled as potential endocrine disruptors. The effect on the development of the neocortex, however, is unknown. To evaluate the neurodevelopmental effects of prenatal DEHP exposure at 1 and 100 mg/kg/day or 100 and 500 mg/kg/day in fetal and newborn mice, we performed a detailed histologic analysis of the developing dorsal telencephalon and neocortex. The observation of fetuses exposed to DEHP revealed reductions of proliferation and neurogenesis (1 and 100 mg/kg) and an increase in cell death (500 mg/kg). In addition, the newborns prenatally exposed to DEHP showed an abnormal neuronal distribution and a decrease in neurons. These findings suggest that prenatal DEHP exposure induces neurodevelopmental toxicity associated with the neural stem cell niche and corticogenesis.
  • Arginine vasotocin neuronal development and its projection in the adult brain of the medaka, Nao Kagawa, Akira Honda, Akiko Zenno, Ryosuke Omoto, Saya Imanaka, Yusuke Takehana, Kiyoshi Naruse, NEUROSCIENCE LETTERS, NEUROSCIENCE LETTERS, 613, 47 - 53, Feb. 2016 , Refereed
    Summary:The neurohypophysial peptide arginine vasotocin (AVT) and its mammalian ortholog arginine vasopressin function in a wide range of physiological and behavioral events. Here, we generated a new line of trans genic medaka (Oryzias latipes), which allowed us to monitor AVT neurons by enhanced green fluorescent protein (EGFP) and demonstrate AVT neuronal development in the embryo and the projection of AVT neurons in the adult brain of avt-egfp transgenic medaka. The onset of AVT expression manifested at 2 days postfertilization (dpf) as a pair of signals in the telencephalon of the brain. The telencephalic AVT neurons migrated and converged on the preoptic area (POA) by 4 dpf. At the same stage, another onset of AVT expression manifested in the central optic tectum (OT), and they migrated to the ventral part of the hypothalamus (VH) by 6 dpf. In the adult brain, the AVT somata with EGFP signals existed in the gigantocellular POA (gPOA), magnocellular POA (mPOA), and parvocellular POA (pPOA) and in the VH. Whereas the major projection of AVT fibers was found from the pPOA and VH to the posterior pituitary, it was also found that AVT neurons in the three POAs send their fibers into wide regions of the brain such as the telencephalon, mesencephalon and diencephalon. This study suggests that the avt-egfp transgenic medaka is a useful model to explore AVT neuronal development and function. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
  • Neurohypophysial Hormones Regulate Amphibious Behaviour in the Mudskipper Goby, Tatsuya Sakamoto, Yudai Nishiyama, Aoi Ikeda, Hideya Takahashi, Susumu Hyodo, Nao Kagawa, Hirotaka Sakamoto, PLOS ONE, PLOS ONE, 10(7), e0134605, Jul. 2015 , Refereed
    Summary:The neurohypophysial hormones, arginine vasotocin and isotocin, regulate both hydromineral balance and social behaviors in fish. In the amphibious mudskipper, Periophthalmus modestus, we previously found arginine-vasotocin-specific regulation of aggressive behavior, including migration of the submissive subordinate into water. This migration also implies the need for adaptation to dehydration. Here, we examined the effects of arginine vasotocin and isotocin administration on the amphibious behavior of individual mudskippers in vivo. The mudskippers remained in the water for an increased period of time after 1-8 h of intracerebroventricular (ICV) injection with 500 pg/g arginine vasotocin or isotocin. The 'frequency of migration' was decreased after ICV injection of arginine vasotocin or isotocin, reflecting a tendency to remain in the water. ICV injections of isotocin receptor antagonist with arginine vasotocin or isotocin inhibited all of these hormonal effects. In animals kept out of water, mRNA expression of brain arginine vasotocin and isotocin precursors increased 3- and 1.5-fold, respectively. Given the relatively wide distribution of arginine vasotocin fibres throughout the mudskipper brain, induction of arginine vasotocin and isotocin under terrestrial conditions may be involved also in the preference for an aquatic habitat as ligands for brain isotocin receptors.
  • Comparative analyses of lysophosphatidic acid receptor-mediated signaling, Nobuyuki Fukushima, Shoichi Ishii, Toshifumi Tsujiuchi, Nao Kagawa, Kazutaka Katoh, CELLULAR AND MOLECULAR LIFE SCIENCES, CELLULAR AND MOLECULAR LIFE SCIENCES, 72(12), 2377 - 2394, Jun. 2015 , Refereed
    Summary:Lysophosphatidic acid (LPA) is a bioactive lipid mediator that activates G protein-coupled LPA receptors to exert fundamental cellular functions. Six LPA receptor genes have been identified in vertebrates and are classified into two subfamilies, the endothelial differentiation genes (edg) and the non-edg family. Studies using genetically engineered mice, frogs, and zebrafish have demonstrated that LPA receptor-mediated signaling has biological, developmental, and pathophysiological functions. Computational analyses have also identified several amino acids (aa) critical for LPA recognition by human LPA receptors. This review focuses on the evolutionary aspects of LPA receptor-mediated signaling by comparing the aa sequences of vertebrate LPA receptors and LPA-producing enzymes; it also summarizes the LPA receptor-dependent effects commonly observed in mouse, frog, and fish.
  • Frequency and size of micronuclei induced in gill cells of medaka fish (Oryzias latipes) after whole-body exposure to clastogenic chemicals, Akinori Takai, Nao Kagawa, Masahiro Nakagawa, Yumi Watabe, Kazuo Fujikawa, DRUG AND CHEMICAL TOXICOLOGY, DRUG AND CHEMICAL TOXICOLOGY, 38(1), 67 - 72, Jan. 2015 , Refereed
    Summary:Medaka fish (Oryzias latipes) were whole-bodily treated with various doses of mitomycin C (MMC), ethylmethanesulfonate (EMS), cyclophosphamide (CP), diethylnitrosamine (DEN), or colchicine (COL) for 24 h, and the frequency of micronucleated cells (MNCs) was measured in the gills at 24 and 48 h after treatment. In the present experiments, MMC, CP, and DEN were recorded as efficient inducers of micronuclei at both sampling times, and none of the MNC frequencies recorded with these agents at 24 h significantly exceeded the corresponding frequency at 48 h. For EMS and COL, positive responses were recorded only 48 h after treatment. By comparison with the time-course data reported for radiation-induced MNCs in the same MN assay system, the clear responses observed at the 48-h time point for all the chemicals used were regarded as evidence of their delayed effects on micronucleus (MN) formation. The mean sizes of micronuclei induced after exposure to COL was significantly larger by a factor 2 as compared with that induced by X-irradiation, whereas those determined for the other four chemicals were almost equal to that induced by X-irradiation. These results demonstrate that the medaka gill-cell MN assay can detect chemically-induced chromosome damage, either directly or after metabolic activation, and spindle malfunction, and provide a basis for further development of the present assay system for testing cytogenetic activities of chemical agents.
  • Functional lysophosphatidic acid receptors expressed in Oryzias latipes, Yuji Morimoto, Shoichi Ishii, Jun-ichi Ishibashi, Kazutaka Katoh, Toshifumi Tsujiuchi, Nao Kagawa, Nobuyuki Fukushima, GENE, GENE, 551(2), 189 - 200, Nov. 2014 , Refereed
    Summary:Lysophosphatidic acid (LPA) signaling is known to play biological and pathophysiological roles in many types of animals. Medaka (Oryzias latipes) is an experimental fish that can be easily maintained, propagated, and analyzed, and whose genome has been completely sequenced. However, there is limited information available regarding medaka LPA receptors. Here, using information from the medaka genome database, we examine the genomic structures, expression, and functions of six LPA receptor genes, Lpar1-Lpar6. Our analyses reveal that the genomic structures of Lpar1 and Lpar4 are different from those deduced from the database. Functional analyses using a heterologous expression system demonstrate that all medaka LPA receptors except for LPA(5b) respond to LPA treatment with cytoskeletal changes. These findings provide useful information on the structure and function of medaka LPA receptor genes, and identify medaka as a useful experimental model for exploration of the biological significance of LPA signaling. (C) 2014 Elsevier B.V. All rights reserved.
  • Newborn mice exposed prenatally to bisphenol A show hyperactivity and defective neocortical development, Munekazu Komada, Saki Itoh, Kota Kawachi, Nao Kagawa, Yayoi Ikeda, Tetsuji Nagao, TOXICOLOGY, TOXICOLOGY, 323, 51 - 60, Sep. 2014 , Refereed
    Summary:The central nervous system is especially susceptible to toxic insults during development. Prenatal administration of bisphenol A (BPA) induces histologic anomalies in the dorsal telencephalon of the embryo. Whether these anomalies affect the morphogenesis and maturation of neuronal function of the newborn neocortex, however, is unknown. To evaluate the neurodevelopmental and behavioral effects of prenatal BPA exposure at 20 and 200 mu g/kg/day in newborn mice, we performed a detailed histologic analysis of the neocortex and tested for the presence of behavioral abnormalities in newborn mice prenatally exposed to BPA using our newly developed behavioral test. Observations of newborn mice prenatally exposed to BPA revealed abnormal neuronal distribution and layer formation, hypoplasia of layer 6b, and abnormal dopaminergic neuronal projections in the neocortex. Further, the newborn mice exhibited hyperactivity. These findings suggest that prenatal BPA exposure induces neurobehavioral toxicity associated with abnormal dopaminergic neuronal projections, and abnormal corticogenesis and lamination. Histologic and behavioral analyses of newborn mice are considered useful for assessing the neurodevelopmental and behavioral toxicity of chemicals. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
  • Comparison of stress response between two wild populations of Japanese medaka, Oryzias latipes and O. sakaizumii, Mao Furuno, Keita Sugimoto, Mai Komori, Nao Kagawa, NIPPON SUISAN GAKKAISHI, NIPPON SUISAN GAKKAISHI, 80(3), 379 - 381, May 2014 , Refereed
  • Early to middle gestational exposure to diethylstilbestrol impairs the development of labyrinth zone in mouse placenta, Nao Kagawa, Yoshiaki Saito, Tetsuji Nagao, CONGENITAL ANOMALIES, CONGENITAL ANOMALIES, 54(2), 116 - 119, May 2014 , Refereed
    Summary:This study was performed to clarify the involvement of impaired labyrinth zone (LZ) of the placenta in the developmental toxicity of diethylstilbestrol (DES). DES at 10g/kg per day was administered orally to mice on days 4 through 8 of gestation. Histological observation of the LZ and determination of blood glucose levels in dam and fetus were performed on day 13. A high frequency of embryonic death was observed in the DES group. DES induced the underdevelopment of the plexus vasculosus, extensive maternal blood space and the decreased expression of glucose transporters in the LZ, and a reduction of the glucose level in embryos. These findings suggest that impaired LZ development may be related to the embryolethality of DES.
  • Early to middle gestational exposure to diethylstilbestrol impairs the development of labyrinth zone in mouse placenta, Nao Kagawa, Yoshiaki Saito, Tetsuji Nagao, CONGENITAL ANOMALIES, CONGENITAL ANOMALIES, 54(2), 116 - 119, May 2014 , Refereed
    Summary:This study was performed to clarify the involvement of impaired labyrinth zone (LZ) of the placenta in the developmental toxicity of diethylstilbestrol (DES). DES at 10g/kg per day was administered orally to mice on days 4 through 8 of gestation. Histological observation of the LZ and determination of blood glucose levels in dam and fetus were performed on day 13. A high frequency of embryonic death was observed in the DES group. DES induced the underdevelopment of the plexus vasculosus, extensive maternal blood space and the decreased expression of glucose transporters in the LZ, and a reduction of the glucose level in embryos. These findings suggest that impaired LZ development may be related to the embryolethality of DES.
  • Neurobehavioral evaluation of mouse newborns exposed prenatally to low-dose bisphenol A, Tetsuji Nagao, Kota Kawachi, Nao Kagawa, Munekazu Komada, JOURNAL OF TOXICOLOGICAL SCIENCES, JOURNAL OF TOXICOLOGICAL SCIENCES, 39(2), 231 - 235, Apr. 2014 , Refereed
    Summary:There have been few neurobehavioral toxicology studies on newborn animals. Thus, we developed a mouse newborn behavioral testing method for evaluating the risk of neurotoxicity of environmental toxicants, by means of determining the newborn's motor activity applying the tare function of an analytical balance. Motor activities including crawling, pivoting, righting or tremors of mouse newborns were evaluated. Tremors of newborns of dams exposed to bisphenol A at 2, 20 or 200 mu g/kg/day on days 5 through 18 of gestation were significantly increased when evaluated on postnatal day 1, as well as those of newborns exposed prenatally to diethylstilbestrol at 0.5 mu g/kg/day. We suggest that our developed testing method may provide a useful addition to neurobehavioral assessment in very young rodents exposed to environmental hormone mimics.
  • Comparison of Aggressive Behaviors Between Two Wild Populations of Japanese Medaka, Oryzias latipes and O-sakaizumii, Nao Kagawa, ZOOLOGICAL SCIENCE, ZOOLOGICAL SCIENCE, 31(3), 116 - 121, Mar. 2014 , Refereed
    Summary:This study compared aggressiveness between two distinct wild populations of Japanese medaka: a Northern population, Oryzias sakaizumii, and a Southern population, O. latipes. When four males competed in intra-population contests, the social hierarchy was determined based on aggressive acts in both populations. Dominants of the Southern population showed higher aggressive acts than did dominants of the Northern population. Increased aggressiveness of Southern males compared with Northern males was also observed when a pair of Northern and Southern males were compared in inter-population contests. High expression of arginine vasotocin (AVT) in distinct preoptic regions were found in dominants and subordinates of the Southern population, but not in those of the Northern population. In contrast, neither 11-ketotestosterone nor cortisol levels in plasma differed between dominants and subordinates of either population, nor between pairs of the Northern and the Southern males. Taken together, these findings indicate that the two wild populations of medaka represent intriguing models for the study of neuroendocrinological correlates in behavioral traits underlying congeners of medaka fish.
  • Newly developed mouse newborn behavioral testing method for evaluating the risk of neurotoxicity of environmental toxicants, Tetsuji Nagao, Nao Kagawa, Munekazu Komada, JOURNAL OF APPLIED TOXICOLOGY, JOURNAL OF APPLIED TOXICOLOGY, 33(12), 1514 - 1519, Dec. 2013 , Refereed
    Summary:Although there have been a vast number of behavioral toxicology studies carried out on adult mice and rats, there have been few neurobehavioral studies utilizing their newborn animals. Thus, we developed a mouse newborn behavioral testing method for evaluating the risk of neurotoxicity of chemicals, by means of determining the newborn's activity using the tare function of an analytical balance. The unstable weighing values resulting from movement of the newborn on the balance recorded by a personal computer every 0.1s, and the total activities of a newborn from the start time of weighing to individual times of evaluation were calculated. In addition, we confirmed the usefulness of our method by determining the activity of mouse newborns with microcephaly induced by prenatal exposure to a neurotoxicant, methylnitrosourea. Copyright (c) 2012 John Wiley & Sons, Ltd.
  • Potential roles of arginine-vasotocin in the regulation of aggressive behavior in the mudskipper (Periophthalmus modestus), Nao Kagawa, Yudai Nishiyama, Kanoko Kato, Hideya Takahashi, Yasuhisa Kobayashi, Hirotaka Sakamoto, Tatsuya Sakamoto, General and Comparative Endocrinology, General and Comparative Endocrinology, 194, 257 - 263, Dec. 01 2013 , Refereed
    Summary:The hypothalamic hormones, arginine-vasotocin (VT) and isotocin (IT), play central roles in osmoregulation and in the regulation of social behaviors including aggressive behavior in many vertebrates including fish. Here, we examined whether these hormones are associated with aggressive behavior in the mudskipper (Periophthalmus modestus). The mudskipper is an amphibious fish, which lives in the brackish water of river mouths and displays unique aggressive behavior. Upon introduction to each other in an experimental tank with aquatic and terrestrial areas, a pair of males can be classified as aggressive dominant or submissive subordinate based on the frequency of their aggressive acts, which is significantly higher in dominant male. Additionally, the length of stay in terrestrial area of dominant was longer than that of the subordinate. The latter remained in aquatic area almost throughout the period of behavioral observation. The expression of brain VT mRNA was significantly higher in subordinate than in dominant, whereas neither IT mRNA expression nor plasma cortisol level differed between subordinate and dominant male. On the other hand, an intracerebroventricular injection of VT increased aggressive behaviors in mudskippers. In addition to known roles of VT in mediation of aggressive behavior, these results may shed light on the role of endogenous VT toward water migration in submissive mudskippers. The amphibious fish is a valuable experimental model to observe the relationship between effects of central VT on the osmoregulation and social behavioral regulation in vertebrates. © 2013.
  • Developmental effects of oral exposure to diethylstilbestrol on mouse placenta, Tetsuji Nagao, Nao Kagawa, Yoshiaki Saito, Munekazu Komada, JOURNAL OF APPLIED TOXICOLOGY, JOURNAL OF APPLIED TOXICOLOGY, 33(11), 1213 - 1221, Nov. 2013 , Refereed
    Summary:Placental growth and function are of biological significance in that placental tissue promotes prenatal life and the maintenance of pregnancy. Exposure to synthetic estrogens causes embryonic mortality and placental growth restriction in mice. The aim of the present study was to examine the effects of diethylstilbestrol (DES) on placenta in mice. DES at 1, 5, 10 or 15 mu g kg(-1) day(-1), or 17-estradiol (E-2) at 50 mu g kg(-1) day(-1), was administered orally to ICR mice on days 4 through to 8 of gestation. Expression of ER, ER, ERR or ERR mRNA in the junctional or labyrinth zone of the placentas on day 13 was assessed using RT-PCR, as well as the embrynic mortality, embryonic and placental weight, histological changes of labyrinth and ultrastructural changes of the trophoblast giant cells (TGCs). Embryo mortalities in the DES 10 and 15 mu g kg(-1) day(-1) groups were markedly increased. No significant changes in embryonic and placental weight were observed in any DES- or E-2-exposed groups. Expression of ER mRNA in the junctional zone with male embryos in the 5 mu g kg(-1) day(-1) group was significantly higher than that in the control, whereas expression was not determined in the 15 mu g kg(-1) day(-1) group. Histological observation revealed that the placentas exposed to DES at 10 mu g kg(-1) day(-1) lacked the developing labyrinth. Ultrastructural observation of the TGCs showed poor rough-surfaced endoplasmic reticulum in the DES 10 mu g kg(-1) day(-1) group. The present data suggest that developmental changes induced by DES may be related to interference with the nutrition and oxygen exchange between mother and embryo or decreased protein synthesis, resulting in a high frequency of embryo mortality. Copyright (c) 2012 John Wiley & Sons, Ltd.
  • Social rank-dependent expression of arginine vasotocin in distinct preoptic regions in male Oryzias latipes, N. Kagawa, Journal of Fish Biology, Journal of Fish Biology, 82(1), 354 - 363, Jan. 2013 , Refereed
    Summary:This study examined arginine vasotocin (AVT) expression in the brains of dominant and subordinate male medaka Oryzias latipes after short- and long-term competition. High AVT expression in distinct preoptic regions was found in dominants and subordinates within minutes of encountering each other. During long-term competition, AVT expression remained high in dominants but not in subordinates. © 2012 The Author. Journal of Fish Biology © 2012 The Fisheries Society of the British Isles.
  • Radiation dose-rate effect on mutation induction in spleen and liver of gpt delta mice., Naohito Okudaira, Yoshihiko Uehara, Kazuo Fujikawa, Nao Kagawa, Akira Ootsuyama, Toshiyuki Norimura, Ken-ichi Saeki, Takehiko Nohmi, Ken-ichi Masumura, Tsuneya Matsumoto, Yoichi Oghiso, Kimio Tanaka, Kazuaki Ichinohe, Shingo Nakamura, Satoshi Tanaka, Tetsuya Ono, Radiation research, Radiation research, 173(2), 138 - 47, Feb. 2010 , Refereed
    Summary:The effect of dose rate on radiation-induced mutations in two somatic tissues, the spleen and liver, was examined in transgenic gpt delta mice. These mice can be used for the detection of deletion-type mutations, and these are the major type of mutation induced by radiation. The dose rates examined were 920 mGy/min, 1 mGy/min and 12.5 microGy/min. In both tissues, the number of mutations increased with increasing dose at each of the three dose rates examined. The mutation induction rate was dependent on the dose rate. The mutation induction rate was higher in the spleen than in the liver at the medium dose rate but was similar in the two tissues at the high and low dose rates. The mutation induction rate in the liver did not show much change between the medium and low dose rates. Analysis of the molecular nature of the mutations indicated that 2- to 1,000-bp deletion mutations were specifically induced by radiation in both tissues after high- and low-dose-rate irradiation. The occurrence of deletion mutation without any sequence homology at the break point was elevated in spleen after high-dose-rate irradiation. The results indicate that the mutagenic effects of radiation in somatic tissues are dependent on dose rate and that there is some variability between tissues.
  • Alteration of genome structure induced by very low dose-rate irradiation in mouse tissues, Tetsuya Ono, Yoshihiko Uehara, Naohito Okudaira, Kazuo Fujikawa, Nao Kagawa, Mitsuaki Yoshida, Isamu Hayata, Takehiko Nohmi, Tsuneya Matsumoto, Yoichi Oghiso, Kimio Tanaka, Kazuaki Ichinohe, Shingo Nakamura, Satoshi Tanaka, Data Science Journal, Data Science Journal, 8, BR36 - BR41, Sep. 24 2009 , Refereed
    Summary:To understand the effects of low dose-rate radiation on genome structure in vivo, we examined gene mutation and chromosomal abnormality in mouse tissues. The mutation was studied on transgenes in the spleen and liver and also on the Dlb1 gene in intestinal stem cells. The mice were irradiated for 483 consecutive days at three dose-rates of 0.0323, 0.65, and 12.5 μGy/min, which resulted in total doses of 21, 414, and 8,000 mGy, respectively. Statistically significant increases were observed for all indices examined when the total dose was 8,000 mGy, whereas no significant difference was observed with 21 mGy or 414 mGy.
  • Relative biological effectiveness of fission neutrons for induction of micronucleus formation in mouse reticulocytes in vivo., Nao Kagawa, Masahiko Shimura, Akinori Takai, Satoru Endo, Kazuo Fujikawa, Mutation research, Mutation research, 556(1-2), 93 - 9, Nov. 22 2004 , Refereed
    Summary:Following whole-body irradiation of ICR mice with various doses of fission neutrons or X-rays, the frequency of micronuclei (MNs) in peripheral blood reticulocytes was measured at 12 h intervals beginning immediately after irradiation and ending at 72 h after irradiation. The resulting time-course curve of MN frequency had a clear peak 36 h after irradiation, irrespective of the type of radiation applied and the dose used. The MN frequency, averaged as the unweighted mean over the experimental time course, showed a linear increase with increasing dose of either fission neutrons or X-rays. The linear response to X-rays supports reported conclusion that induction of MN formation in reticulocytes is a dose-rate independent phenomenon. The relative biological effectiveness (RBE) of fission neutrons to X-rays for MN induction was estimated to be 1.9 +/- 0.3. This value is considerably lower than the RBE value of 4.6 +/- 0.5 reported for the same fission neutrons for induction of lymphocyte apoptosis in the thymus of ICR mice that represents dose-rate independent, one-track event. Based on these results, we propose that MNs increased in reticulocytes after irradiation mostly represent acentric fragments caused by single chromosome breaks, and that some confounding factor is operating in erythroblasts for the formation of aberrations from non-rejoining DNA double-strand breaks more severely after high-LET radiation than after low-LET radiation.
  • A drastic reduction in the basal level of heat-shock protein 90 in the brain of goldfish (Carassius auratus) after administration of geldanamycin., Nao Kagawa, Zoological science, Zoological science, 21(11), 1085 - 9, Nov. 2004 , Refereed
    Summary:Geldanamycin (GA), a specific inhibitor of the chaperoning function of heat-shock protein 90 (Hsp90), has been shown to mimic heat shock (HS) in inducing expression of Hsp90, Hsp72 and other Hsps in unstressed mammalian cells. In the present study, intra-cerebral treatment of goldfish with GA (at a dose of 0.1 microg/g-body weight) diminished basal Hsp90 level to a 30-40% level in the brain, without affecting the basal Hsp72 level, as assayed 28-48 h after treatment. Whole-body exposure to HS significantly increased Hsp90 level in GA-untreated fish but not in GA-treated fish, while it significantly increased Hsp72 level in both GA-untreated and -treated fish. In both GA-untreated and -treated fish, plasma cortisol (PC) levels increased considerably 4 h after HS and then decreased in a time-dependent manner to the control levels 24 h after HS, showing no evidence of a GA effect on the time course of PC level. These results suggest that in the brain of goldfish, Hsp90 may not be involved as a key factor either in regulating Hsp72 expression both before and after HS or in the feedback regulation of HS-increased PC level, and support the idea that GA can be used in fish brain as a tool in elucidating the role of Hsp90 in complicated, Hsp-mediated biological processes.
  • Susceptibility of male and female medaka (Oryzias latipes) fish to spontaneous and X-ray induced micronucleus formation in gill cells, Akinori Takai, Nao Kagawa, Kazuo Fujikawa, Mutation Research - Genetic Toxicology and Environmental Mutagenesis, Mutation Research - Genetic Toxicology and Environmental Mutagenesis, 558(1-2), 131 - 136, Mar. 14 2004 , Refereed
    Summary:The frequency of micronucleated cells (MNCs) was measured in acridine-orange (AO) stained RNA-rich gill cells from male and female medaka (Oryzias latipes) fish of known body weight. Spontaneous MNC frequencies were not significantly correlated with body weight, despite the fact that the heaviest of the 30 fish used outweighed the lightest by a factor of 3. Average MNC frequencies were identical in males and females at 0.8‰. An X-ray dose of 4Gy increased the frequency of MNCs over the spontaneous level in all 30 of the fish used, reaching a level of 7.2‰ on average when assayed 24h after exposure. In X-ray treated fish, MNC frequency and body weight were not significantly correlated, nor was there any difference between the sexes. These and other results support our primary conclusion that AO-staining is suitable for the medaka micronucleus assay in gill cells, and indicate that male and female medaka fish are similarly and size-independently susceptible to both spontaneous and X-ray induced micronucleus formation in gill cells. © 2003 Elsevier B.V. All rights reserved.
  • Susceptibility of male and female medaka (Oryzias latipes) fish to spontaneous and X-ray induced micronucleus formation in gill cells., Akinori Takai, Nao Kagawa, Kazuo Fujikawa, Mutation research, Mutation research, 558(1-2), 131 - 6, Mar. 14 2004 , Refereed
    Summary:The frequency of micronucleated cells (MNCs) was measured in acridine-orange (AO) stained RNA-rich gill cells from male and female medaka (Oryzias latipes) fish of known body weight. Spontaneous MNC frequencies were not significantly correlated with body weight, despite the fact that the heaviest of the 30 fish used outweighed the lightest by a factor of 3. Average MNC frequencies were identical in males and females at 0.8 per thousand. An X-ray dose of 4 Gy increased the frequency of MNCs over the spontaneous level in all 30 of the fish used, reaching a level of 7.2 per thousand on average when assayed 24 h after exposure. In X-ray treated fish, MNC frequency and body weight were not significantly correlated, nor was there any difference between the sexes. These and other results support our primary conclusion that AO-staining is suitable for the medaka micronucleus assay in gill cells, and indicate that male and female medaka fish are similarly and size-independently susceptible to both spontaneous and X-ray induced micronucleus formation in gill cells.
  • Dose- and time-dependent responses for micronucleus induction by X-rays and fast neutrons in gill cells of medaka (Oryzias latipes)., Akinori Takai, Nao Kagawa, Kazuo Fujikawa, Environmental and molecular mutagenesis, Environmental and molecular mutagenesis, 44(2), 108 - 12, 2004 , Refereed
    Summary:Medaka fish (Oryzias latipes) were exposed to various doses of X-rays or fast neutrons, and the frequency of micronucleated cells (MNCs) was measured in gills sampled at 12- or 24-hr intervals from 12 to 96 hr after exposure. The resulting time course of MNC frequency was biphasic, with a clear peak 24 hr after exposure, irrespective of the kind of radiation applied and the dose used. The half-life of MNCs induced in the gill tissues by the two exposures fluctuated around 28 hr, with no significant dose-dependent trend for either X-ray- or neutron-exposed fish. As assayed 24 hr after exposure, the MNC frequency increased linearly over the control level with increasing doses of both X-rays and fast neutrons. The relative biological effectiveness (RBE) of fast neutrons to X-rays for MNC induction was estimated to be 4.3 +/- 0.6. This value is close to the RBE value of 5.1 +/- 0.3 reported for fast neutron induction of somatic crossing-over mutations in Drosophila melanogaster that arise from recombination repair of DNA double-strand breaks. These results and other data support our conclusion that the medaka gill cell micronucleus assay is a reliable short-term test for detecting potential inducers of DNA double-strand breaks.
  • Increased incidence of malformations in the offspring of male mice prenatally exposed to synthetic estrogens., Tetsuji Nagao, Nao Kagawa, Madoka Nakagomi, Kazuo Fujikawa, Advances in experimental medicine and biology, Advances in experimental medicine and biology, 518, 211 - 7, 2003 , Refereed
  • Brain HSP70 mRNA expression is linked with plasma cortisol levels in goldfish (Carassius auratus) exposed to a potential predator., Nao Kagawa, Yasuo Mugiya, Zoological science, Zoological science, 19(7), 735 - 40, Jul. 2002 , Refereed
    Summary:We previously found that when goldfish were exposed to a potential predator, bluegills, the goldfish experienced an increase in HSP70 mRNA expression in the brains and increased plasma cortisol levels. In the present study, we examined the potential causative relationship between HSP70 mRNA expression and plasma cortisol levels. Cortisol agonists (corticotropin releasing factor and cortisol) and antagonists (metyrapone and betamethasone) were used to modulate plasma cortisol levels. HSP70 mRNA expression and plasma cortisol levels were analyzed by Northern blotting and ELISA, respectively. Goldfish treated with the cortisol agonists showed marked increases in plasma cortisol levels and also in brain HSP70 mRNA expression. When goldfish were exposed to bluegills, plasma cortisol levels increased and HSP70 mRNA expression was enhanced after 6 hr. However, pre-treatment with the cortisol antagonists 24 hr prior to the exposure inhibited the enhancement as well as the increase in plasma cortisol levels. These results suggest that plasma cortisol plays a key role in the enhancement of brain HSP70 mRNA expression in goldfish stressed by exposure to bluegills.
  • Stress protein 70 expression and plasma cortisol levels in psychologically stressed goldfish, Carassius auratus, Nao Kagawa, Yasuo Mugiya, Fisheries Science, Fisheries Science, 68, 1315 - 1316, 2002 , Refereed
  • Exposure of goldfish (Carassius auratus) to bluegills (Lepomis macrochirus) enhances expression of stress protein 70 mRNA in the brains and increases plasma cortisol levels, Nao Kagawa, Yasuo Mugiya, Zoological Science, Zoological Science, 17(8), 1061 - 1066, 2000 , Refereed
    Summary:The effect of psychological stress on HSP70 mRNA in the brains and plasma cortisol levels in goldfish was examined. Stress was induced by exposure to a predator (bluegills). HSP70 mRNA and cortisol were determined by Northern blotting and ELISA, respectively. Goldfish exposed to four predators in the same tank without a partition showed marked increases in HSP70 mRNA and cortisol levels 6 hr and 12 hr after commencement of exposure. When goldfish were separated from bluegills with a net partition, HSP70 mRNA expression was enhanced after 6 hr, and returned to the control level after 12 hr. Plasma cortisol levels increased after 2 hr, and returned to the control level after 6 hr. When goldfish were placed in a transparent tank around which bluegills were swimming, HSP70 mRNA expression and cortisol levels increased after 6 hr and 12 hr. Goldfish exposed to water circulating through a tank with bluegills showed no sign of changes in HSP70 mRNA expression or cortisol levels. These results suggest that psychological stress enhanced HSP70 mRNA expression in the brains and increased plasma cortisol levels via visual perception.
  • Enhanced expression of stress protein 70 in the brains of goldfish, Carassius auratus, reared with bluegills, Lepomis macrochirus, N. Kagawa, K. Ryo, Y. Mugiya, Fish Physiology and Biochemistry, Fish Physiology and Biochemistry, 21(2), 103 - 110, 1999 , Refereed
    Summary:Induction of stress protein (HSP70) was studied in goldfish (Carassius auratus) reared with bluegills (Lepomis macrochirus), a predator of small fish. HSP70 was identified by Western blotting and quantified by optical density after SDS-PAGE. The expression of HSP70 was significantly enhanced in the brains of goldfish reared with bluegills for 6 and 12 h in a single tank. The hepatopancreas and the kidney were not affected by the treatment. When goldfish were separated from bluegills with a partition net (1 × 1 cm mesh size), this protein also increased in the brains after 6 h but then returned to the control level after 12 h. When the goldfish and bluegills were kept in separate tanks and were not able to see each other but were connected by circulating water, HSP70 levels in the goldfish were unaffected. Immunohistochemical observations indicated that an anti-HSP70 antibody was found to react predominantly with the optic and vagal lobes of the brains. These results suggest that visual perception plays a primary role in enhancement of HSP70 expression in the goldfish reared with bluegills.

Works

  • Stress physiology in fish

Misc

  • III-1. Aggressive behavior and hormones in fish, Nao Kagawa, Nippon Suisan Gakkaishi (Japanese Edition), 81, 5, 869,   2015 , 10.2331/suisan.81.869