ABSTRACT Similarity in reproductive functions between non-human primates and humans makes non-human primates generally serve as better experimental animals in reproductive researches. Cynomolgus monkeys show such similarity in their menstrual cycle patterns of serum luteinizing hormone (LH), follicle-stimulating hormones (FSH), and sex steroid hormones. Although similarities include significant increase in serum estradiol (E2) concentrations just before ovulation, cynomolgus monkeys differ in their negligible increase in E3 and single increase in progesterone (P) during the luteal phase. Unique to humans and great apes (e.g., gorillas and chimpanzees) are apparently biphasic patterns in serum E2 concentrations at the periovulatory period and at the luteal phase and synchronous increases in serum concentrations of P with E2 at the luteal phase. Although humans and non-human primates differ in their secretory activity of steroid hormones from the functional corpus luteum, they share the same controlling mechanism of the function of the corpus luteum by LH, based on our analysis of the LH-receptor characteristics throughout the menstrual cycle of cynomolgus monkeys. Although humans and cynomolgus monkeys show similarities in the fluctuation patterns of maternal serum concentrations of sex steroid hormones during the pregnancy period, they differ in the fluctuation patterns of protein hormones. For cynornolgus monkeys, maternal serum concentrations of chorionic gonadotropin (CG) and sornatomammotropin (i.e.. placental lactogen, or CS) increase only in the first quarter of pregnancy. However, for humans, higher serum concentrations of those two hormones (CG and CS) are maintained throughout the entire pregnancy. Similarities and differences among non-human primates and humans are discussed in this article.
ABSTRACT Interferon alfacon- 1 (Infergen<, CIFN, r-metIFN Conl, hereunder interferon alfacon-I ) is a type I interferon currently used to treat patients infected with the hepatitis C virus. In order to assess the embryotoxic and teratogenic effects of interferon alfacon-I, doses of 0, I, 3 and 10 pg/kg/day were administered subcutaneously to pregnant rhesus monkeys daily from Day 20 to Day 50 of gestation. No maternal deaths occurred, and no interferon alfacon- 1 related abnormalities were noted in general signs, body weight, food consumption or necropsy findings in any group. Abortions and embryonic deaths occurred in 4 out of the 10 dams of the 3 pg/kg/day group and 8 out of the 10 dams of the 10 pg/kg/day group between Days 25 and 62 of gestation. The concentrations of serum 17D-estradiol and/or progesterone levels decreased before embryonic death in some, but not all monkeys in the 3 and 10 ,ug/kg/day groups. Microscopic changes to the uterus and placenta in the dams that experienced embryonic/fetal cardiac arrest included hemorrhage and necrosis in the chorionic villi, hemorrhage in the uterine gland, granular leukocyte infiltration, hemorrhage and/or thrombus in the endometrium. In the surviving fetuses, no test article related abnormalities were observed in body weight. placental weight, external measurements, organ weights, external, placental, visceral or skeletal findings. The mean serum concentration of interferon alfacon-1 at 10 pg/kg/day was consistent with previous pharmacokinetic data in non-pregnant rhesus monkeys, suggesting that pregnancy does not greatly alter the pharmacokinetics of interferon alfacon- 1. Antibodies to interferon alfacon-1 were first detected on Day 40 of gestation in all groups receiving the drug.
It was concluded that the non-toxic maternal dose level of interferon alfacon-1 is 10 pgkglday. Doses of interferon alfacon-1 of 3 and 10 pg/kg/day were associated with an increase in abortiodembryonic death rate, but 1 ,ug/kg/day did not result in any effect on the fetus. No teratogenic or growth retardation effect from interferon alfacon-1 was observed in the surviving fetuses at 10 pgkglday.
ABSTRACT To establish a treatment for Treacher Collins syndrome, the maxillocraniofacial morphology was quantitatively evaluated by means of cephalometric radiography and the following results were obtained. I. The cranial base showed a small value of S-ER’ (length of sphenoid bone in anterior cranial base), S-SOS’ (length of sphenoid bone in posterior cranial base) and S-Ba (length of posterior cranial base) in addition to similarly reduced NSBa, indicating undergrowth of the the cranial base as well. 2. Though the orbit had large BIOD and BIODfW with ocular hypertelorism, no abnormal finding was obtained in the antero-posterior positioning of the orbit in the skull. 3. In the maxillary region, the maxilla showed undergrowth but no abnormal finding was recorded on the vertical and antero-posterior positioning of the mandible. 1. The mandible showed undergrowth with a wide mandibular angle. In conclusion, the morphology evaluated quantitatively in patients with Treacher Collins syndrome varied considerably. Therefore, it was considered essential to evaluate the morphology accurately for treating this syndrome including surgery and orthodontic treatment.
ABSTRACT Cases with congenital abnormalities were evaluated in the inpatient and outpatient materials of A1 Mafraq Hospital in the United Arab Emirates between 1992 and 1994. The quality of data and diagnostic skill were appropriate. The baseline birth prevalence of total congenital abnormalities was 38.9 per 1000 which corresponded to the international figures based on nearly complete ascertainment. The cases of inpatient clinic may represent the general features of congenital abnormalities in the United Arab Emirates and particular clusters of different congenital abnormalities were not found.
ABSTRACT 3-Chloro-4-( dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is known as a by-product of wood pulp manufacture and a contaminant of chlorinated drinking water. Since our previous studies (Teramoto et al.. 1998, 1999) demonstrated in a micromass in lirro test a strong inhibitory effect of MX on rat embryo cell differentiation, the potential teratogenicity was investigated in this study by using a suspension organ culture system. Twelve-day mouse embryo palatal explants were cultivated for 77- hr in the MX-containing medium at a concentration of 0, I, 10, 100 or 300 pglml and examined for closure of the palatal shelves. All control explants showed almost complete closure of the palatal shelves. Similar results were also obtained in the MX-treated explants at concentrations up to and including 100 pglml. Immunohistochemistry revealed no difference between the control and MX-treated explants in distribution of PCNA- and TUNEL-positive cells in the palatal mesenchyme and medial edge epithelium. respectively. When the MX concentration was raised to 300 pglml, palatal shelves remained wide open. However, histopathology revealed extensive pyknosis of the mesenchymal cells and loss of the epithelium. These results may indicate that MX is cytotoxic against the mouse palate at a high concentration, and that it has no cleft-palate inducing effects in mice.
ABSTRACT The purpose of the study was to check the human teratogenic potential of penicillin V: oral penamecillin treatment during pregnancy in the population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996. The pairs of cases with congenital abnormalities and their matched population controls without congenital abnormalities were evaluated, in addition the data of total population and of patient control groups as referents were compared with the data of congenital abnormality groups. In the three study groups there were 38,151 pregnant women who had newborn infants without any defects (population control group), 27,865 pregnant women who had newborns or fetuses with congenital abnormalities, and 812 mothers of informative offspring with Down syndrome (patient controls). In the population control group 2,246 (5.9%) pregnant mothers were treated with penamecillin, in the case group 1,597 (7.0%) pregnant women had penamecillin treatment while in the patient control group 63 (7.9%) mothers used penamecillin during pregnancy. The use of penamecillin treatments during pregnancy was higher in the total case (i.e., congenital abnormality) group, than in the total population control group. However, the highest use of oral penamecillin was found in the patient control group. The case-matched population control pair analysis did not show a higher use of medically documented penamecillin during the second-third months of pregnancy, i.e., in the critical period for most major congenital abnormalities. In addition, an association between medically documented penamecillin use during the second and third months of gestation and different congenital abnormality groups was not found when total population control group or patient control groups were used as referent. Thus, the reported higher use of penamecillin among the mothers of cases and patient controls can be explained mainly by recall bias. Thus, treatment with oral penamecillin during pregnancy did not indicate detectable teratogenic risk to the fetus
ABSTRACT Bis-diamine is known to induce congenital anomalies including cardiac defects, thymic hypoplasia and snout defects in rat embryos. Cardiovascular lesions consist of persistent truncus arteriosus, tetralogy of Fallot and aortic arch anomalies, which are often found in DiGeorge syndrome. In the the present study, we investigated effects of bis- diamine on cardiac neural crest cells, which may be important to the teratogenecity. A single dose of 200 mg bis-diamine was administered to pregnant rats at 10.5 embryonic day (ED). lmmunohistochemical studies were performed on embryos at 11.5, 12.5 and 13.5 ED using anti-HNK-1 and anti-N-CAM antibodies. The embryos at 11.5 and 12.5 ED showed the similar distributional patterns of either HNK-1 or N-CAM positive cells in control and bis-diamine treated embryos. N-CAM immunoreactivities in the splanchnic mesoderm were quite weakly detectable in the bis-diamine treated embryos at 12.5 ED. Closure of the neural tube was delayed in the treated embryos at this period. Immunohistochemistry of the control embryos at 13.5 ED demonstrated a continuous chain of N-CAM expression between the neural plexus near the foregut and the fourth aortic arch, while no apparent continuity of N-CAM positive tissue was observed in the bis-diamine treated embryos. These findings suggested that bis-diamine reduced the amount of neural crest cells which appeared to participate in the aortic arch formation or conotruncal septation. The primary effect of bis-diamine in the induction of various congenital anomalies including cardiovascular malformations may be an inhibition of the normal development of the neural tube and neural crest.
ABSTRACT To evaluate the effects of potential estrogenic or anti-estrogenic compounds on reproduction, male and female Sprague-Dawley rats were injected subcutaneously with 50 pg/kg diethylstilbestrol (DES) or 20 mg/kg tamoxifen (TAM) from postnatal day 1 to 5. Growth, estrous cycle, locomotor activity, and reproductive function including masculine sexual behavior, sperm motion, and development of reproductive organs were examined. Decrease in body weight gain and abnormal estrous cycle, such as persistent estrous, or prolonged estrous cycle were observed following early neonatal exposure to DES or TAM, while there was no effect on locomotor activity evaluated in the open field in the DES- or TAM-treated group. A marked decrease in sperm motility was found in the TAM-treated group. Anatomical and histological alterations of reproductive organs were observed in male and female rats in the DES-treated group and in female rats in the TAM-treated group. Early neonatal exposure to DES or TAM affected the masculine sexual behavior, resulting in a marked decrease in the ability to copulate and in fertility. In matings of the DES- or TAM-treated rats and intact rats, none of the treated females copulated successfully, whereas approximately 30% of treated males showed normal fertility. These results suggested that early neonatal exposure to DES or TAM induced more marked reproductive dysfunction after puberty in females than in males.
ABSTRACT Male ICR strain mice were injected intraperitoneally with ENU at 50 mg/kg daily for 5 days and mated to untreated virgin females of the same strain on days 64-80 after the last dose. Copulations during this period involved spermatogonial stem cells at the time of the last treatment. Subsequently, copulated females were injected intraperitoneally with ENU at 25-100 mg/kg on day 8 of gestation, at 50-200 mg/kg on day 12 of gestation or injected subcutaneously with triamcinolone acetonide at 1.25-10 mgkg on day 12 of gestation. The uterine contents were examined on day 18 of gestation. Fetuses of dams treated on day 8 of gestation were inspected for external and skeletal abnormalities, and those of dams treated on day 12 were inspected for external abnormalities including cleft palate. Frequencies of microphthalmia and cleft palate in the group in which females mated with ENU-treated males were treated with ENU at 50 mg/kg on day 8 of gestation or with ENU at 50 mg/kg on day 12 of gestation, respectively, were significantly higher than those in the group in which females mated with phosphate buffer-treated males were treated with ENU at 50 mgkg on day 8 or at 50 mg/kg on day 12. No significant increases in the frequency of cleft palate were observed in the groups in which females mated with ENU- treated males were treated with triamcinolone acetonide on day I:! of gestation as compared with groups in which females mated with phosphate buffer-treated males were treated with triamcinolone acetonide on day 12 of gestation. These results suggested the increased susceptibility to induced teratogenesis (congenital malformations induced by exposure of embryo/fetus during gestation) in the offspring derived from paternal germ cells treated with the potent mutagen ENU, but not the non-mutagen triamcinolone acetonide.