Yojiro Ooshima

Shin Nippon Biomedical Laboratories, Ltd., Kagosima, Kagoshima, Japan

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Publications (18)21.46 Total impact

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    ABSTRACT: Thiamazole, an anti-hyperthyroidism agent, was administered orally to pregnant cynomolgus monkeys at doses of 2.0 and 3.5 mg/kg per day from GD 120 to GD 150 to investigate effects on behavioral development of their infants. Swelling of the throat region due to enlargement of the thyroid glands was observed at birth in thiamazole-treated infants, and it returned to normal around postnatal day (PND) 30. At necropsy of infants at 12 months of age, thyroidal weight in the thiamazole groups was increased. This finding suggested the likelihood that administration of thiamazole to maternal animals during the late gestational period induced thyroid goiter in fetal/infant monkeys through placental transfer of thiamazole. No clear changes were noted in thyroid histopathology or serum thyroid hormone levels in maternal animals or infants, but goiter formation might have been indicative of exposure to high thyroid stimulating hormone (TSH) and low T3 or T4 in utero from maternal treatment with thiamazole. Age-related changes were observed in the control in behavioral development tests, while infants at 3.5 mg/kg showed no age-related decrease in contact behavior and no increase in exploratory activity on PND 90 or PND 170. In addition, the number of eye contacts between PND 210 and PND 240 was less frequent. This indicated that maternal exposure to thiamazole induced mental retardation-like behaviors in infants. Thiamazole may directly inhibit thyroid hormone synthesis in the fetus by placental transfer. From these results, it was speculated that oral administration of thiamazole to maternal animals during the late gestational period induced retardation of behavioral development in their infants.
    Congenital Anomalies 12/2013; 53(4):149-54.
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    ABSTRACT: Japan Association for Laboratory Animal Medicine (JALAM) recommends humane handling of rat fetuses. However, it is a challenge to accept proposed euthanizing methods such as cervical dislocation, decapitation and/or intracardiac injection of potassium chloride, because these methods would damage fetal specimens for skeletal and visceral examinations in developmental toxicity studies. The present study aimed at seeking better methodologies for fetal euthanasia and anesthesia. We were unable to accomplish fetal euthanasia directly, but instead, we could euthanize fetuses under pain-controlled anesthesia. It is recommended that hypothermia by immersion in cold physiological saline is an appropriate method for anesthesia. Moreover, we recommend that the anesthetized fetuses should be euthanized immediately by removal of the vital organs or immersion in appropriate fixatives.
    Congenital Anomalies 03/2013; 53(1):46-48.
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    Reproductive Toxicology 11/2012; 34(3):487. · 3.14 Impact Factor
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    ABSTRACT: The testes from 136 male cynomolgus monkeys were examined histopathologically in order to investigate the relationship between the development of spermatogenesis and testis weight, age, and body weight. At Grade 1 (immature), Sertoli cells and spermatogonia were the only cell classes in the testis. At Grade 2 (pre-puberty), no elongated spermatids were observed in the testis, although a few round spermatids and small lumen formation were observed. At Grade 3 (onset of puberty), all classes of germ cells were observed in the testis, although seminiferous tubule diameters and numbers of germ cells were small. Slight debris in the epididymis was observed in almost all animals. At Grade 4 (puberty), almost complete spermatogenesis was observed in the seminiferous tubules and it was possible to ascertain the spermatogenesis stage as described by Clermont, although tubule diameters and numbers of germ cells were small. There was less debris in the epididymis than at Grade 3. At Grade 5 (early adult), complete spermatogenesis was observed in the seminiferous tubules. At Grade 6 (adult), complete spermatogenesis in the seminiferous tubules and a moderate or large number of sperm in the epididymis were observed. Moreover, sperm analysis using ejaculated sperm was possible. Logistic regression analysis showed that testis weight is a good indicator of testicular maturity.
    Toxicologic Pathology 05/2012; 40(6):935-42. · 2.06 Impact Factor
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    ABSTRACT: We previously reported on a histological classification of cynomolgus monkey testis into six grades (1, immature; 2, prepuberty; 3, onset of puberty; 4, puberty; 5, early adult; 6, adult) based on spermatogenesis development. In this investigation, the accessory reproductive organs from the same animals underwent histomorphometric examination, in addition to being examined histologically and weighed, to evaluate relationships between these parameters and the six grades. Seminiferous tubule diameter increased corresponding to the testicular maturity grade and was notably increased at grade 6. Beginning from grade 3, increases in the areas of the ductus epididymis were noted, and reserved sperm was visible in the lumen. In the prostate, the glandular lumen area per unit area showed an increase beginning from grade 3 but no clear differences between grades 4 and 6; advanced development of epithelial height was observed at grade 6. In the seminal vesicle, development of the epithelial cell layer was markedly increased at grade 6. It was concluded that development of the male accessory reproductive organs began after reserved sperm was observed in the lumen of the ductus epididymis (grade 3) and that these organs were developed notably when the testis reached sexual maturity (grade 6).
    Toxicologic Pathology 05/2012; 40(6):918-25. · 2.06 Impact Factor
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    ABSTRACT: We investigated the effects that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure has on the prostate in rhesus monkey offspring. Dams received 0, 30 or 300 ng/kg TCDD subcutaneously on Day 20 of gestation, and then 5% of the initial dose was injected every 30 days until Day 90 after delivery. The offspring were maintained until reaching sexual maturity, and examined histopathologically. Dose-dependent decreases in glands of the prostate and widespread fibrosis were observed in offspring. It is noteworthy that 7 years from the final lactational TCDD exposure, inflammatory cell infiltration and disruption of glands of the prostate were still observed. Differential mRNA expression associated with fibrosis, inflammatory response and disruption of cell components were demonstrated by microarray analysis, with up-regulation of TGM4, TGFB1, COL1A1 and MMP2 confirmed. In conclusion, in utero and lactational exposure to TCDD induced dose-related prostatic fibrosis, indicating prostatic dysfunction and inducible semen quality reduction in second-generation rhesus monkeys.
    Reproductive Toxicology 06/2010; 29(3):317-22. · 3.14 Impact Factor
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    ABSTRACT: The objective of juvenile animal toxicity studies of pharmaceuticals is to obtain safety data, including information on the potential for adverse effects on postnatal growth and development. Studies in juvenile animals may assist in identifying postnatal developmental toxicities or other adverse effects that are not adequately assessed in the routine toxicity evaluations and that cannot be safely or adequately measured in pediatric clinical trials. Unlike the traditional reproductive and developmental toxicology studies that have been discussed in the accompanying reports, the design requirements for toxicity studies in juvenile animals are not explicitly defined in regulatory guidance. However, studies in juvenile animals can be useful in providing safety information necessary to enable pediatric clinical trials in pediatric patients or when there are special concerns for toxicities that cannot be safely or adequately measured in clinical trials. These juvenile animal toxicity studies are designed on a case-by-case basis. General design considerations and examples of study designs for assessment of juvenile animal toxicity are discussed.
    Birth Defects Research Part B Developmental and Reproductive Toxicology 12/2009; 86(6):463-9. · 1.97 Impact Factor
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    ABSTRACT: Assessment of potential developmental and reproductive toxicity of human pharmaceuticals is currently guided by the International Conference on Harmonization (ICH) S5(R2) document (available at http://www.ich.org). The studies that assess developmental hazard are generally conducted in rodents and rabbits. Based on the authors' collective experience, adequate designs (including range-finding studies) and the presentation of data for these studies are described in detail. In addition, the suggested initiation and then total duration of these studies in relation to clinical studies that enroll women of childbearing potential are described. Optional parameters that may be included in the studies are discussed, as are study designs that combine assessments of fertility and developmental toxicity. New methods that may replace or enhance current procedures are outlined. The details described herein will assist all laboratories performing these studies, individuals who need to plan for the studies, and regulatory agencies that ultimately review these studies.
    Birth Defects Research Part B Developmental and Reproductive Toxicology 12/2009; 86(6):418-28. · 1.97 Impact Factor
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    ABSTRACT: Developmental and reproductive toxicology testing in nonhuman primates (NHPs) has become more common due to the increasing number of biopharmaceuticals in drug development, since NHPs are frequently the only species to express pharmacologic responses similar to humans. NHPs may also be used to help resolve issues associated with small-molecule reproductive toxicology in traditional species (rodents and rabbits). Adequate designs in NHP are presented for developmental toxicity (embryo-fetal development, pre-postnatal development, enhanced pre-postnatal development), reproductive toxicity (male and female), and juvenile toxicity studies. Optional parameters that may be included in these studies are discussed, as are new study designs that consolidate multiple aspects of the reproductive assessment and thereby conserve the limited supply of sexually mature NHPs available for testing. The details described will assist scientists in pharmaceutical, regulatory, and contract research organizations who are involved in conducting these unique studies to optimize their design based on case-by-case considerations.
    Birth Defects Research Part B Developmental and Reproductive Toxicology 12/2009; 86(6):446-62. · 1.97 Impact Factor
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    ABSTRACT: This update (Version 2) of the Terminology of Developmental Abnormalities in Common Laboratory Mammals (Version 1) incorporates improvements and enhancements to both content and organization of the terminology to enable greater flexibility in its application, while maintaining a consistent approach to the description of findings. The revisions are the result of an international collaboration among interested organizations, advised by individual experts and the outcomes of several workshops. The terminology remains organized into tables under the broad categories of external, visceral, and skeletal observations, following the manner in which data are typically collected and recorded in developmental toxicity studies. This arrangement of the tables, as well as other information provided in appendices, is intended to facilitate the process of specimen evaluation at the laboratory bench level. Only the commonly used laboratory mammals (i.e. rats, mice, rabbits) are addressed in the current terminology tables. The inclusion of other species that are used in developmental toxicity testing, such as primates, is considered outside the scope of the present update. Similarly, categorization of findings as, for example, 'malformation' or 'variation' remains unaddressed, in accordance with the overall principle that the focus of this document is descriptive terminology and not diagnosis or interpretation. The skeletal terms have been augmented to accommodate cartilage findings.
    Congenital Anomalies 09/2009; 49(3):123-246.
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    ABSTRACT: A long-term developmental toxicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure was performed in rhesus monkeys and the effect on male reproductive organs was determined in the second generation. Dams received 0, 30 or 300 ng/kg TCDD subcutaneously on Day 20 of gestation, and then 5% of the initial dose was injected every 30 days until Day 90 after delivery. The offspring were maintained until reaching sexual maturity, and evaluated by semen analysis, and histopathology of the testes and epididymides. Ejaculated sperm concentration was severely reduced at 300 ng/kg, and sperm viability and activity were dose-proportionally reduced, although effects on spermatogenesis were slight. Histomorphometry revealed markedly reduced area of the ductus epididymis accompanying decreased reserved sperm in the 30 and 300 ng/kg groups. In conclusion, in utero and lactational exposure to TCDD induced a reduction of sperm quality in rhesus monkeys.
    Reproductive Toxicology 09/2009; 28(4):495-502. · 3.14 Impact Factor
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    ABSTRACT: ABSTRACT  Aniline hydrochloride (AH), a methemoglobin formation-stimulating substance, at a dosage level of 520 mg/kg which does not induce apparent fetal death, was injected subcutaneously into pregnant rats once on day 14, 15 or 16 of gestation in order to assess the stage specificity of cleft palate induction. Also, doses of 260, 390, 520 and 650 mg/kg were administered to pregnant rats on day 15 of gestation, and the dose-response relationships with respect to fetal cleft palate and maternal methemo-globinemia induction were studied. In the stage-specificity study, paleness, decreased body weight gain and elevated methemoglobin concentration were noted in the dams treated with AH. Upon fetal examinations, although reduced body weight was noted in all AH-treated groups, cleft palate was observed only in fetuses from those dams treated on day 15 of gestation. In the dose-dependency study, AH induced maternal methemoglobinemia, decreased fetal body weight and increased the incidence of cleft palate dose dependently when administered at dosage levels of 260, 390, 520 and 650 mg/kg on day 15 of gestation. Additionally, administration of methylene blue, a methemoglobinemia-preventing substance, to the AH-treated dams ameliorated maternal methemoglobinemia and reduced the incidence of fetal cleft palate. In summation, it is considered that AH stage-specifically induces cleft palate in rats and that cleft palate is caused not by a direct teratogenic effect of AH but by maternal hypoxia due to methemoglobinemia.
    Congenital Anomalies 06/2008; 41(2):112 - 117.
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    ABSTRACT: ABSTRACT  Aniline hydrochloride (AH), a methemoglobin-formation stimulating substance, at a dosage level that does not induce apparent fetal death was injected subcutaneously into pregnant rats once a day on days 6–8, 9–11, 12–14 or 15–17 of gestation in order to assess its ability to stage-specifically produce cardiovascular malformations. In addition, AH at dosage levels of 195, 260, 325 and 395 rag/kg was injected into pregnant rats subcutaneously once a day on days 12–14 of gestation, and the dose-dependent induction of ventricular septal defect (VSD) in relation to maternal methemoglobinemia was studied. In the stage-specificity study, paleness, decreased body weight gain and elevated methemoglobin concentration were noted in the dams. Upon fetal examination, reduced body weight was noted in all AH-treated groups. AH induced cardiovascular malformations, mainly VSD, which was most frequently observed in the day 12–14 group and also observed in the day 15–17 group. Abnormal branching of subclavian, pulmonary and vertebral arteries were most frequently observed in the day 9–11 group. In the dose-dependency study, AH induced maternal methemoglobinemia, decreased fetal body weight and increased the incidence of VSD dose dependency. Additionally, administration of methylene blue, a methemoglobinemia-preventing substance, to the AH-treated dams ameliorated maternal methemoglobinemia and reduced the incidence of fetal VSD. From these results, it is considered that AH stage-specifically induces cardiovascular defects, mainly VSD, in rats and that VSD is induced not by a direct teratogenic effect of AH but by maternal hypoxia due to methemoglobinemia.
    Congenital Anomalies 06/2008; 41(2):118 - 123.
  • Yojiro OOSHIMA, Toshio IHARA
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    ABSTRACT: Abstract Embryopathy in yellow KK mice with non-insulin dependent diabetes mellitus was examined among the conceptuses of females mated at 7, 11, and 13 weeks of age.The numbers of corpora lutea and implants were comparable in all maternal age groups. Early embryonic deaths were frequently observed in all maternal age groups (37.7 46.4%), but no significant difference was found among the groups. The incidence of late embryonic deaths was significantly higher in 11- and 13-wk-old dams (25.6% and 28.8%) than in 7-wk-old dams (14.4%). Moreover, in 13-wk-old dams, but not in 7-wk-old dams, a positive correlation existed between maternal plasma glucose levels on day 18 of pregnancy and late embryonic deaths. Fetuses from 13-wk-old dams weighed less than those from 7-wk-old dams (0.73 g vs 0.86 g).Yellow KK mice mated at 13 weeks of age were treated with an oral-hypoglycemic agent, 5-[4-(l-methylcyclohexylmethoxy)benzyl] thiazolidine-2,4-dione (ciglitazone), as an 0.1% dietary admixture. Plasma glucose on day 18 of pregnancy was lower in all treated groups (159-170 mg/dl) than in the untreated control (345 mg/dl). A significant decrease of late embryonic deaths (12.7-15.6%) and a slight increase of fetal weights (0.79-0.81 g) were noted when compared with the untreated controls (36.8% and 0.74 g).
    Congenital Anomalies 05/2008; 26(3):169 - 177.
  • Yojiro OOSHIMA, Kohei SHIOTA, Toshio IHARA
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    ABSTRACT: Yellow KK mice have the Ay allele and spontaneously develop non-insulin dependent diabetes mellitus (NIDDM). In the present study, female yellow KK mice were mated at 7 or 13 weeks of age (the average blood glucose levels were ca. 260 and 500 mg/dl, respectively), and their fetuses were examined on days 18 or 19 of gestation.The fetuses from 13-wk-old dams were smaller than those from 7-wk-old dams. The average lung weight on day 19 of gestation was slightly greater in the fetuses from 13-wk-old dams than in those from 7-wk-old dams (23.3 vs 21.2 mg). Histologically, alveolar spaces were smaller and alveolar walls were thicker in the fetuses from 13-wk-old dams than in those from 7-wk-old dams. Morphometric analysis revealed that the percentage area of the fetal lung occupied by alveolar spaces was significantly smaller in the former fetuses than in the latter.Day-15 fetal lungs of KK mice, which do not have the Ay allele, were cultured in hyperglycemic media (glucose levels: 400 and 700 mg/dl) for 48 hr. The development of alveoli was inhibited in hyperglycemic media as compared to the development of the lungs grown in the control medium. The inhibitory effect was dependent on the glucose concentration in the media.Thus, it seems that maternal hyperglycemia itself is a major cause of the delayed maturation of the fetal lung in NIDDM mice.
    Congenital Anomalies 05/2008; 31(1):33 - 40.
  • Yojiro OOSHIMA
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    ABSTRACT: Yellow KK mice with non-insulin dependent diabetes were mated at 7 (group A) or 13 (group B) weeks of age. On day 13, 16, or 18 of pregnancy, the plasma glucose concentration in dams was determined, and the embryos/fetuses and placentae were weighed and examined.The rate of early embryonic death was high and invariable on all three days. The rate of late death increased with advancing pregnancy in both groups and the incidence in group B was higher than in group A on each of the three days. On day 13 of pregnancy, maternal plasma glucose concentration in group B was significantly higher than in group A (465mg/dl vs 230 mg/dl). Embryonic and placental weights in group B were less than those in group A (84 vs 113 mg and 59 vs 68 mg). In group B, there was an inverse correlation between the maternal plasma glucose concentration and the embryonic weight. A similar inverse correlation existed between the maternal plasma glucose concentration and the placental weight. On days 16 and 18 of pregnancy, fetal weights in group B were less than those in group A, but placental weights did not differ significantly between the two groups.From these results, it appears that in the yellow KK mouse fetal growth retardation has already begun in the organogenesis period and is closely related to maternal hyperglycemia.
    Congenital Anomalies 05/2008; 31(1):13 - 21.
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    ABSTRACT: Bouin's or a 10% formalin solution has been used to fixate internal fetal observations for developmental toxicity studies in rats. However, these fixatives are known to cause contraction of the ventricle of the heart and arteries, which makes dissection and observation more difficult. Fetuses on day 20 of gestation from pregnant Crj:CD(SD)IGS rats were injected with 10 w/v% magnesium chloride/10 vol% neutral buffered formalin solution into the thoracic cavity, and then fixed in 10 vol% neutral buffered formalin. After fixation, the heart was dissected using a modified Staples technique. In treated fetuses, the membranous region of the ventricular septum and the valves were clearly observed in an expanded state. We conclude that this method increases the ability to detect heart anomalies and decreases the chance of a false-positive finding.
    Congenital Anomalies 04/2005; 45(1):32-4. · 1.00 Impact Factor
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    ABSTRACT: In September 2003, a new revision of the draft guideline (Organization for Economic Co-operation and Development [OECD] Guideline for the Testing of Chemicals, Proposal for a New Guideline 426, Developmental Neurotoxicity Study) was distributed. The draft guideline consists of 51 paragraphs and an appendix. The National Coordinators were requested to arrange national expert reviews of the guideline proposal in their member countries. The member of the Behavioral Teratology (BT) Committee of the Japanese Teratology Society (JTS) reviewed, discussed and commented on the draft Test Guideline proposal. The BT Committee of the JTS also commented that the International Collaborative Study to validate this protocol should be definitely performed. These comments were sent to the OECD Secretariat. The BT Committee of the JTS expects that the comments are useful for further discussion.
    Congenital Anomalies 10/2004; 44(3):172-7. · 1.00 Impact Factor