ABSTRACT Infertility is defined as a couples failure to conceive following 2 years of unprotected sexual intercourse, affects 10% of reproductive age couples in Japan. There are 3 main causes: (1) ovarian failure-anovulation (29%); (2) tubal factor-anatomic defects of the female genital tract (36%); (3) male factor-abnormal spermatogenesis (31%). The goal of the infertility evaluation are to determine the probable cause of infertility regarding prognosis and to provide guidance regarding options for treatment In the event an obstruction of the fallopian tubes is discovered or spermatogenesis cannot be improved, assisted reproductive technologies (ART) such as gamete intrafallopian tube transfer (GIFT) and in vitro fertilization with embryo transfer (IVF-ET) are recommended. Since the successful birth of Louise Brown by this IVF-ET, an explosion of ART has occurred all over the world in the last decade. In this review we discuss the revolution brought about by ART focusing on results in Japan, and clarify ethical issues that must be resolved.
ABSTRACT The Japanese Behavioral Teratology Meeting, a satellite meeting of the Japanese Teratology Society, proposed a core battery of tests to detect behavioral teratogens in animals in 1992. The core battery consists of examining maternal body weight, offspring weight, external anomalies, viability, preweaning landmarks of physical development (pinna, incisor and eyelids), preweaning reflex tests (surface righting, negative geotaxis and mid-air righting), an open-field test at 5 weeks of age, a water-filled multiple T-maze (Biel-type water maze) test at 6 weeks, a shuttlebox test at 7 weeks and brain weight at termination on postnatal day 56. In order to evaluate the detectability of behavioral dysfunction in rat offspring by this core battery, the first collaborative study was carried out in 1993 using phenytoin. The present, second collaborative study using retinoic acid (RA) was performed in twenty-eight laboratories to further evaluate the proposed core test battery. Pregnant SD rats received 5 mg/kg RA orally from days 14 to 16 of gestation, and postnatal development of their offspring was evaluated. The effects of RA on offspring were detected as lower viability, increased incidence of minor anomalies in the paw and nail, delayed pinna detachment, negative geotaxis and air righting, and less frequent rearing and grooming behaviors in the open-field test. However, no effects were observed in the Biel-type maze and shuttlebox tests. These results suggest that our proposed core battery of tests is useful as a screening method to detect postnatal development disorders, including behavioral dysfunction, in SD rat offspring exposed to RA in utero.
ABSTRACT In order to directly compare the malformation complex induced by genetic and environmental factors, mouse trisomy 16 (Ts 16) fetuses and bis-diamine treated (BDT) mouse fetuses in which pregnant females were orally dosed with 3.0 mg and 1.0 mg/B.W. (g) bisdiamine eight hours apart on 9 days of pregnancy, were examined. Cystic hygroma with generalized edema appeared in most Ts 16 and in less than 50% of BDT fetuses. Blunt snout or facial cleft with aplasia or hypoplasia of the olfactory bulb was observed in BDT fetuses. The thymus was markedly to moderately hypoplastic in Ts 16, and absent or markedly hypoplastic in BDT fetuses. Parathyroid glands were inclined to be unsettled in relative location to the thyroid in Ts 16 and absent in BDT fetuses. Aortic arch abnormalities were present in approximately half of the cases of Ts 16 and in the majority of cases of BDT fetuses. In the conotruncal region, double outlet right ventricle and persistent truncus arteriosus were dominantly observed in Ts 16 and BDT fetuses, respectively. Atrioventricular septal defect was observed in every Ts 16 and in about 30% of BDT fetuses. These results indicate that not only environmental factors but also genetic factors can experimentally induce DiGeorge-Iike anomaly in mice. Abnormal development relevant to neural crest cells seems to occur typically in BDT fetuses, and incompletely in Ts 16 fetuses.
ABSTRACT Human embryos were studied to clarify controversies surrounding the developmental morphology of the basal ganglia and related structures. Eleven human embryos at Carnegie stages 12 through 21 were examined and reconstructed by the three-dimensional computer graphics technique. Findings on the neural morphology and telencephalic arteries reveal that (1) all parts of the basal ganglia and the amygdala are telencephalic structures; (2) the medial part of globus pallidus, preoptic area and medial septal nucleus originate from the medial ganglionic eminence; (3) the olfactory bulb, prepiriform area, caudate head, caudate body, caudate tail, nucleus accumben septi, putamen, lateral part of globus pallidus and the amygdala originate from the lateral gangiionic eminence.
ABSTRACT This study investigated the effects of ethinyl estradiol (EE) and bisphenol-A (BPA) on the maturation of fetuses, reproductive organ, brain development, and behavior. Twenty-eight Jcl-ICR pregnant mice were divided into 0.2 mg/kg of EE, 0.02 mg/kg of EE, BPA and control groups. Pregnant mice belonging to 0.2 mg/kg of EE and 0.02 mg/kg of EE group were daily injected subcutaneously either 0.2 mg/kg or 0.02 mg/kg of EE dissolved in olive oil from 11 to 19 days of gestation. The BPA group received an injection of 100 mg/kg of BPA dissolved in olive oil while the control group received an injection of olive oil alone subcutaneously on the same days of gestation. Neurological and behavioral development was examined by means of the sensorimotor reflexes until day 10 and openfield test on day 40 after birth. Myelination of the brain and maturation of testis were histologically examined. Obtained results were: 1) Pregnant mice in the 0.2 mg/kg EE group had no live births. 2) The mean litter size in the 0.02 mg/kg EE group was smaller than that in the BPA and control groups. The mean body weight at birth and that at the age of 60 days showed no significant differences among groups. 3) In the openfield test at the age of 40 days, the mean number of grooming and line-crossing in the inner field in the 0.02 mg/kg EE group were significantly higher than those in the control group and the mean number of grooming, rearing and line-crossing in the outer field in 0.02 mg/kg EE group were significantly higher than those in the BPA group. The mean numbers of defecation in both 0.02 mg/kg EE group and BPA group were less than those in the control group. 4) The mean diameter of seminiferous tubules and number of spermatocytes layers in the 0.02 mg/kg EE group and BPA were significantly less than those in the control group. 5) The mean diameter of tractus mamillothalamics in the 0.02mg/kg EE group and BPA group showed no significant differences compared with that in the control group. These findings suggested that prenatal exposure to EE or BPA adversely affects litter size, openfield behavior and spermatogenesis.
ABSTRACT Maldevelopment of the brain in offspring whose mothers drank and/or smoked during pregnancy was evaluated using Japanese data. The diagnostic criteria for fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE) revealed that FAS infants exhibited a severer degree of CNS involvement than FAE infants. In addition to the criteria for fetal tobacco syndrome (FTS), we proposed the term “fetal tobacco effects (FTE)” for when the gestational age is less than 37 weeks. Maldevelopment of the brain was not severer in FTS than FTE, to which factors other than smoking causing a reduction in the gestational period, and ones during pregnancy and delivery may contribute. The effects on the CNS of alcohol were more frequent and severer than those of tobacco. CNS involvement was shown to increase with increasing consumption of alcohol or tobacco.
ABSTRACT The timing of implantation was investigated in Kbl:NZW rabbits to assess the appropriate period of administration of test compounds recommended in the ICH Guideline for reproductive and developmental toxicity studies. After copulating in the morning (day 0 of gestation), pregnant rabbits were euthanized in the morning daily on days 6–9 of gestation. Their uteri were morphologically examined and the process of implantation was investigated. On day 6 of gestation, blastocysts had fixed their position in the uterine lumen for implantation, but they had not yet attached to the uterine mucosa. On day 7 of gestation, implantation sites were macroscopically recognized as protrusions of the uterine wall. Histological examination revealed that ob-placental implantation occurs in the antimesometrial region on days 7 and 8, while placental implantation occurs in the mesometrial region on days 8 and 9 of gestation. It was also found that organogenesis progresses in parallel with implantation.