Hatano Research Institute

Hadano, Japan

Hatano Research Institute

Hadano, Japan

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Muneoka K.,Showa University | Muneoka K.,Chiba University | Kuwagata M.,Hatano Research Institute | Ogawa T.,Showa University | Shioda S.,Showa University
Life Sciences | Year: 2010

Aims: The early neonatal period is critical for the development of the rodent brain. Neurosteroid levels in the brain decline from the late gestation to the neonatal period. Previous studies indicate effects of neurosteroid treatment during the neonatal period on the development of the dopaminergic system. In this study, we investigated the sex-specific effects of neonatal treatment with the neurosteroid progesterone on monoamine metabolism. Separately, we examined the contribution of pre-pubertal castration on the effect of neonatal treatment of pregnenolone (a neurosteroid precursor). Main methods: Progesterone (Experiment 1) or pregnenolone (Experiment 2) treatments in Sprague-Dawley rats were performed from postnatal days 3 through 7. Castration in experiment 2 was performed in male rats at postnatal day 21. We measured the brain tissue contents of dopamine, serotonin (5-HT), and their metabolites in rats at age 10. weeks. Key findings: Results showed that neonatal progesterone treatment altered striatal 5-hydroxy-3-indolacetic acid/5-HT ratios in males and females in opposite directions, in addition to dopaminergic effects. The treatment also influenced dopamine and 5-HT metabolism without sex-specificity in the frontal cortex. In addition, there was no significant difference in striatal monoamine metabolism between sham-operated, castrated and castrated pregnenolone-treated group. Significance: The present result indicates a sex-specific influence of progesterone during the early neonatal period on the development of the serotonergic system, depending on brain region in addition to of the dopaminergic system. © 2010 Elsevier Inc.

Senuma M.,Hatano Research Institute | Mori C.,Chiba University | Ogawa T.,Saitama University | Kuwagata M.,Hatano Research Institute
International Journal of Developmental Neuroscience | Year: 2014

Prenatal arsenite exposure has been associated with developmental disorders in children, including reduced IQ and language abnormalities. Animal experiments have also shown that exposure to arsenite during development induced developmental neurotoxicity after birth. However, the evidence is not enough, and the mechanism is poorly understood, especially on the exposure during early brain development. This study assessed effects of sodium (meta) arsenite shortly after exposure on early developing fetal rat brains.Pregnant rats were administered 50. mg/L arsenite in their drinking water or 20. mg/kg arsenite orally using a gastric tube, on gestational days (GD) 9-15. Fetal brains were examined on GD16.Pregnant rats administered 20. mg/kg arsenite showed reductions in maternal body weight gain and food consumption during treatment, but not with 50. mg/L arsenite. Arsenite did not affect fetal development, as determined by body weight, mortality and brain size. Arsenite also did not induce excessive cell death or affect neural cell division in any region of the fetal neuroepithelium. Thyrosine hydroxylase immunohistochemistry revealed no difference in the distribution of catecholaminergic neurons between fetuses of arsenite treated and control rats. However, reductions in the number of serotonin positive cells in the fetal median and dorsal raphe nuclei were observed following maternal treatment with 20. mg/kg arsenite. Image analysis showed that the serotonin positive areas decreased in all fetal mid- and hind-brain areas without altering distribution patterns. Maternal stress induced by arsenite toxicity did not alter fetal development. These results suggest that arsenite-induced neurodevelopmental toxicity involves defects in the early development of the serotonin nervous system. © 2014 ISDN.Published by Elsevier Ltd.

PubMed | Hatano Research Institute, Tottori University, Hokkaido University, Kamakura Women's University and 2 more.
Type: | Journal: Scientific reports | Year: 2016

Thalidomide is a teratogen in humans but not in rodents. It causes multiple birth defects including malformations of limbs, ears, and other organs. However, the species-specific mechanism of thalidomide teratogenicity is not completely understood. Reproduction of the human teratogenicity of thalidomide in rodents has previously failed because of the lack of a model reflecting human drug metabolism. In addition, because the maternal metabolic effect cannot be eliminated, the migration of unchanged thalidomide to embryos is suppressed, and the metabolic activation is insufficient to develop teratogenicity. Previously, we generated transchromosomic mice containing a human cytochrome P450 (CYP) 3A cluster in which the endogenous mouse Cyp3a genes were deleted. Here, we determined whether human CYP3A or mouse Cyp3a enzyme expression was related to the species difference in a whole embryo culture system using humanized CYP3A mouse embryos. Thalidomide-treated embryos with the human CYP3A gene cluster showed limb abnormalities, and human CYP3A was expressed in the placenta, suggesting that human CYP3A in the placenta may contribute to the teratogenicity of thalidomide. These data suggest that the humanized CYP3A mouse is a useful model to predict embryonic toxicity in humans.

Honma M.,Japan National Institute of Health Sciences | Takahashi T.,Hatano Research Institute | Asada S.,Hatano Research Institute | Nakagawa Y.,Hatano Research Institute | And 2 more authors.
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2012

Carbon nanomaterials such as carbon nanotubes, graphene, and fullerenes (C60) are widely used in industry. Because of human health concerns, their toxic potential has been examined in vivo and in vitro. Here we used mammalian cells to examine the in vitro clastogenicity as well as the phototoxicity of C60. While C60 induced no structural chromosome aberrations in CHL/IU cells at up to 5mg/ml (the maximum concentration tested), it significantly induced polyploidy at 2.5 and 5mg/ml with and without metabolic activation. In BALB 3T3 cells, C60 showed no phototoxic potential but the anatase form of titanium oxide did. Since insoluble nanomaterials cause polyploidy by blocking cytokinesis rather than by damaging DNA, we concluded that the polyploidy induced by C60 in CHL/IU cells was probably due to non-DNA interacting mechanisms. © 2012 Elsevier B.V.

Yakabe T.,Kagome Co. | Takashima H.,Hatano Research Institute | Kuwagata M.,Hatano Research Institute | Fukao M.,Kagome Co. | And 2 more authors.
Food and Chemical Toxicology | Year: 2011

Lactobacillus brevis KB290 (KB290), a plant-derived probiotic lactic acid bacterium, improves gut health and stimulates immune function. Here we extensively investigated the teratogenicity of KB290 in rats and rabbits. We observed no adverse maternal or fetal effects and concluded that the no observable adverse effect level for maternal general toxicity, maintenance of pregnancy, and teratogenicity should be ≥1010cfu/kg/day. Our results suggest that KB290 would be safe for pregnant females and their offspring. © 2010 Elsevier Ltd.

Shimada Y.,Hokko Chemical Industry Co. | Sui H.,Hatano Research Institute | Wako Y.,LSI Corporation | Kawasako K.,LSI Corporation
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2015

The micronucleus induction by p-dimethylaminoazobenzene (DAB), a genotoxic rat liver carcinogen, was assessed in the liver and bone marrow of young adult rats after the repeated administration of DAB for 14 (Lab. 1) and 28 (Lab. 2) days. Three dose levels, 25, 50 and 100. mg/kg/day, were used for the investigations in both labs.The frequency of micronucleated hepatocytes was significantly increased in a dose-dependent manner after the repeated administration of DAB at 50. mg/kg/day or more for 14 and 28 days. Similarly, the frequency of micronucleated immature erythrocytes in the bone marrow was increased after the repeated administration of DAB at 100. mg/kg/day for 14 and 28 days.These results indicate that the repeated-dose liver micronucleus assay allowed for the detection of micronucleus induction by DAB, and that the lowest detectable dose for micronucleus induction in the liver was lower than in the bone marrow. Thus, the repeated-dose liver micronucleus assay using young adult rats is considered suitable for the detection of micronucleus induction by liver carcinogens, such as DAB. © 2014 Elsevier B.V.

Sui H.,Hatano Research Institute | Matsumoto H.,Hatano Research Institute | Wako Y.,LSI Corporation | Kawasako K.,LSI Corporation
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2015

The repeated-dose liver micronucleus (RDLMN) assay has the potential to detect liver carcinogens and can be integrated into general toxicological studies. In this study, thioacetamide (TAA) was tested in 14- and 28-day RDLMN assays to assess the performance of the assay.The test substance, TAA, was administered orally to 6-week-old male Crl:CD (SD) rats once daily for 14 or 28 days at a dosage of 5, 10 or 20. mg/kg/day. Hepatocytes were collected approximately 24. h after the last TAA administration, and the incidence of micronuclei was assessed. In this study, bone marrow micronucleus assays were also conducted in the same animals. The 14- and 28-day RDLMN assays indicated that none of the TAA dosages significantly increased the proportion of micronucleated hepatocytes. Bone marrow micronucleus assays with TAA also provided negative results. It is known that TAA is a liver carcinogen in mice and rats. In the previous genotoxic studies, the Ames test and the chromosomal aberration test using CHL/IU cells have yielded negative results [1-4]. The liver micronucleus assay using young adult rats singly dosed with TAA (75 and 150. mg/kg) also produced negative results [5]. TAA gave positive results only in the mouse bone marrow micronucleus assays [6,7]. © 2014 Elsevier B.V.

Muneoka K.,Showa University | Kuwagata M.,Hatano Research Institute | Ogawa T.,Showa University | Shioda S.,Showa University
Cerebellum | Year: 2015

Neurodevelopmental impairment in the serotonergic system may be involved in autism spectrum disorder. Yokukansan is a traditional herbal remedy for restlessness and agitation in children, and mother–infant co-administration (MICA) to both the child and the nursing mother is one of the recommended treatment approaches. Recent studies have revealed the neuropharmacological properties of Yokukansan (YKS), including its 5-HT1A (serotonin) receptor agonistic effects. We investigated the influence of YKS treatment on behavior in a novel environment and on brain monoamine metabolism during the nursing period in an animal model of neurodevelopmental disorders, prenatally BrdU (5-bromo-2′-deoxyuridine)-treated rats (BrdU-rats). YKS treatment did not influence locomotor activity in BrdU-rats but reduced grooming in open-field tests. YKS treatment without MICA disrupted the correlation between locomotor behaviors and rearing and altered levels of serotonin and its metabolite in the cerebellum. These effects were not observed in the group receiving YKS treatment with MICA. These data indicate a direct pharmacological effect of YKS on the development of grooming behavior and profound effects on cerebellar serotonin metabolism, which is thought to be influenced by nursing conditions. © 2014, Springer Science+Business Media New York.

Ohta R.,Hatano Research Institute | Ohmukai H.,Hatano Research Institute | Toyoizumi T.,Hatano Research Institute | Shindo T.,Hatano Research Institute | And 2 more authors.
Reproductive Toxicology | Year: 2014

In a previous study, we found that early life exposure to low-dose diethylstilbestrol (DES) induced early onset of spontaneous abnormalities in estrus cycle and shortened survival in female Sprague-Dawley rats. In order to confirm the repeatability of the previous study, neonates of C57BL/6J mice were orally administered DES at doses of 0.005, 0.05, 0.5 and 5. μg/kg/day, and the aging of their reproductive function was observed. As a result, delayed toxicity on ovarian function was found in females treated with 0.5. μg/kg/day of DES. Concomitantly, the females in the 0.05. μg/kg/day of DES, or greater, groups, had increased body weights and, in the 0.5. μg/kg/day of DES, or greater, groups, had developed pituitary tumors, which were causal factors in their accelerated mortality. Thus, we found that early life exposure to low-dose DES induced early onset of spontaneous abnormalities in estrus cycle not only in female rats but also in female mice. © 2014 Elsevier Inc.

PubMed | Hatano Research Institute
Type: Journal Article | Journal: Journal of toxicologic pathology | Year: 2016

Although Hatano high-avoidance and low-avoidance rats (HAA and LAA, respectively) have been selectively bred for good versus poor avoidance learning, HAA rats are known to be more reactive to stress than LAA rats. In this study, HAA and LAA female rats were compared during reproductive aging by observing estrous cycles from 8 to 11 months of age. Furthermore, these rats were allowed to live out their natural lifespans, that is, until 24 months of age, in order to compare their survival and to clarify the relationship between reproductive aging and tumor development. At eight months of age, 2 of 35 HAA rats and 20 of 35 LAA rats had abnormal estrous cycles. The median lifespan of the HAA rats (673 days) was shorter than that of the LAA rats (733 days). The incidence of pituitary neoplasia was higher in the HAA rats than in the LAA rats. These results suggest that HAA female rats (i.e., stress-reactive rats) have a shorter lifespan than LAA female rats (i.e., stress-nonreactive rats) and develop pituitary neoplasia, which was one of the causal factors in their accelerated mortality. However, the onset of an age-matched abnormal cycle did not correspond with their lifespan.

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