ABSTRACT Thalidomide was originally developed in 1954 as a sedative that was commonly used to ameliorate morning sickness. However, thalidomide exposure during the first trimester of pregnancy caused multiple birth defects (e.g. phocomelia and amelia), affecting ∼10 000 children worldwide in the late 1950s and early 1960s. Thalidomide is now recognized as a clinically effective, albeit strictly restricted, drug for the treatment of leprosy and multiple myeloma. Investigators have studied thalidomide teratogenicity for half a century, proposing over 30 hypotheses to account for its actions. Among these, the anti-angiogenesis and oxidative stress models have gained widespread support. Nonetheless, the precise molecular mechanisms and direct targets of thalidomide have not heretofore been elucidated. We developed ferrite-glycidyl methacrylate beads that enable magnetic separation and efficient purification of ligand-binding molecules; the beads were recently employed to identify cereblon as a primary target of thalidomide. Cereblon forms an E3 ubiquitin ligase complex with DDB1, Cul4A, and Roc1, which is important for the expression of fibroblast growth factor 8, an essential regulator of limb development. Expression of a drug binding-deficient mutant of cereblon suppressed thalidomide-induced effects in zebrafish and chicks. This suggests that thalidomide downregulates fibroblast growth factor 8 expression and induces limb malformation by binding to wild-type cereblon, inhibiting the function of the associated E3 ubiquitin ligase. The present review summarizes the teratogenicity of thalidomide, including existing models for its mode of action, and discusses the identification of cereblon as a key molecule for deciphering the longstanding mystery of thalidomide teratogenicity.
ABSTRACT Aneuploidy is one of the most common and serious pregnancy complications in humans. Most conceptuses with autosomal aneuploidy die in utero, resulting in early pregnancy loss. However, some fetuses with aneuploidy survive to term but suffer from disorders associated with congenital anomalies and mental retardation, such as Down syndrome with trisomy 21. Three general characteristics of this condition are well acknowledged: (i) in most cases the extra chromosome is of maternal origin; (ii) most cases are derived from a malsegregation event in meiosis I; and (iii) the frequency of these errors increases with maternal age. The basis for the age-dependent increase in meiosis I errors has been a long-standing enigma. Many investigators have addressed the nature of this biological phenomenon through genomic analyses of extra chromosome 21 using polymorphic markers to determine the frequency or location of crossovers that should ensure faithful chromosome segregation. Cytogenetic analyses of in vitro unfertilized oocytes have also been performed. However, no definitive conclusions regarding meiosis I errors have yet been reached from such studies. Recent findings in conditional knock-out mice for meiosis-specific cohesin have shed further light on this issue. The present review focuses on the current understanding of age-related aneuploidy and provides an overview of the mechanisms involved. We refer to recent data to illustrate some of the new paradigms that have arisen in this field.
ABSTRACT Cynomolgus monkey (Macaca fascicularis) is a popular laboratory primate belonging to Old World monkeys, which are the group most closely related to humans except for the apes. This paper summarizes a series of our studies regarding the development of cerebral sulci and gyri in this primate, and the stated possibility of evaluation of the sulcal development for assessing the developmental toxicity testing. The cerebrum of cynomolgus monkeys experienced a regular sequence of emergence of sulci and gyri on gross observation while such timetables corresponded to those obtained by magnetic resonance imaging (MRI) with a lag time of 10–30 days. When the timetables for the emergence of anatomically identical primary sulci and gyri were compared between cynomolgus monkeys and humans, their chronological sequences were comparable, while some sulci and gyri located on the phylogenetically newer cortical region in humans emerged earlier in monkeys. The present paper further indicates brief procedures for evaluating cerebral abnormalities and/or maturity using brain specimens without MRI measurements. The primary sulcal lengths measured by the ‘cotton thread’ method were a brief index of the degree of regional gyrification. As the development of a calcarine sulcus was closely correlated with morphological maturation of the lateral ventricle, which changed drastically during embryonic days (EDs) 90–100, the cerebral maturity on ED 100 could be evaluated by the infolding of that sulcus. Thus, the present paper provides gross anatomical and MRI references and brief procedures for investigating the normality of the development of cerebral sulci and gyri of laboratory primates, cynomolgus monkeys.
ABSTRACT A two-generation reproduction toxicity study was conducted in rats with a reference estrogenic pesticide, methoxychlor, to validate the sensitivity and competency of current guidelines recommended by the United States Environmental Protection Agency; Japanese Ministry of Agriculture, Forestry and Fisheries; and Organisation for Economic Co-operation and Development for predicting reproductive toxicity of the test compound based on estrogenic endocrine disrupting effects. Both sexes of SD rats were exposed to methoxychlor in the diet at concentrations of 0, 10, 500 and 1500 ppm for two successive generations. The present study has successfully detected estrogenic activities and reproductive toxicities of methoxychlor, as well as its systemic toxicity. Body weights, body weight gains and food consumption of both sexes of animals were suppressed significantly in the 500 and 1500 ppm groups. Typical reproductive toxicities observed in females of these groups included, but were not limited to, prolonged estrous cycle, reduced fertility, decreased numbers of implantation sites and newborns, decreased ovary weights and/or increased incidences of cystic ovary. Uterine weights of weanlings increased significantly in these groups, suggesting that the sensitivity of this parameter for predicting estrogenic ability of the test compound is comparable to that of the uterotrophic assay. Reproductive toxicities of methoxychlor seemed less potent in males than in females. Methoxychlor delayed preputial separation and significantly reduced sperm counts and reproductive organ weights of males of the 500 and/or 1500 ppm groups; however, most males that failed to impregnate females in the same group showed normal fertility when they were re-mated with untreated females. Neither systemic nor reproductive toxicities appeared in the 10 ppm group.
ABSTRACT IS-Tlk/Kyo, a rat mutant strain derived from IS/Kyo strain, exhibits a kinked and/or short tail, in addition to a congenital anomaly of the lumbar vertebrae that is a hallmark of IS/Kyo rats. Homozygotes (Tlk/Tlk) of Tlk dominant gene are known to die during embryonic development. The present report deals with the morphological features of heterozygous IS-Tlk/Kyo rat fetuses in comparison with those of IS/Kyo rat fetuses. One of the morphological features was a high incidence of tail vertebral anomalies in IS-Tlk rats (81.6% versus 0% in IS/Kyo rats). Significantly low values in number of live fetuses and ossified 5th sternebra and sacral and caudal vertebrae were observed in IS-Tlk/Kyo rats compared with those in IS/Kyo rats as well as a low incidence of fetuses with ventral septal defects in IS-Tlk/Kyo (0% versus 54.4% in IS rats). These results suggest that the Tlk gene may be involved in the formation of the vertebral centra and the ventral septum when it expresses on the genetic background of the IS rat.
ABSTRACT Understanding the causes of congenital anomalies is of prime importance to develop management and/or prevention strategies. It is widely accepted that the occurrence of congenital malformations in fetuses and neonates is heavily correlated with maternal genetic makeup and lifestyle. However, very few epidemiologic analyses have been conducted on the embryonic developmental period because of the rarity of data available. Instigated in 1961, the Kyoto Collection of Human Embryos comprises approximately 45 000 specimens of embryos and fetuses. The collection's most unique feature is that most specimens were added to the collection along with epidemiologic information on the respective mothers. This is the first report on the digitization of data from the collection. A total of 22 262 embryonic specimens were selected on the basis of data integrity. Data related to the embryos were then classified according to the following criteria: developmental stage, sampling period, geographical area, maternal determinant, and external malformation. Results indicate that 7.8% of the embryos exhibit external anomalies and 92.2% are without anomalies. The three most common anomalies were nuchal bleb, holoprosencephaly and spina bifida. A special emphasis was placed on the potential association between maternal determinants and embryonic external anomalies, allowing for statistical analyses. The present study provides further evidence that this collection represents a unique source of information to conduct epidemiological analyses, not only to further the understanding of congenital anomalies but also to help establish preventive health guidelines for pregnant women.
ABSTRACT The development of the brain vesicles between Carnegie stages (CS) 17 and 23 was analyzed morphometrically using 177 magnetic resonance image data derived from the Kyoto Collection of Human Embryos. Whole embryonic volume was 106.55 ± 21.08 mm3 at CS17, exponentially increasing to CS23 when it reached 1357.28 ± 392.20 mm3. Length of brain vesicles was 29.83 ± 2.52 mm at CS17, increased almost linearly and reached 49.31 ± 6.66 mm at CS23. The rate of increase was approximately 4.2 times higher on the dorsal side than on the ventral side. The increase in the length of the brain vesicles resulted mainly from that of the prosencephalon, and the rate of increase was three times higher on the dorsal side than on the ventral side of the prosencephalon.
ABSTRACT Amniotic band sequence (ABS) is a rare cause of fetal disruptions associated with fibrous bands that entrap various fetal parts in utero and lead to abnormalities. Fetal disruptions of ABS are influenced by the timing of the amnion rupture and the site of amnion adherence. Herein we report an extreme case of ABS presented with dysmorphic face, amputation of four extremities and fusion of legs and genitalia with a fibrotic band. This is an extreme case of ABS characterized by an unusual combination of multiple fetal anomalies.
ABSTRACT The occurrence of four gastrointestinal (GIT) anomalies in a single patient is extremely rare. Only one report of four GIT anomalies in a child has been published in the English literature. The current report presents a child with four anomalies and discusses the molecular mechanisms which control the development of the gastrointestinal tract.
ABSTRACT Severe anomalies of the forebrain together with reduction limb anomalies are a rare congenital anomalies association. We report a prenatal diagnosis of acalvaria, anencephaly and thumb agenesis in a voluntary terminated fetus and discuss the role of genetic counseling.