Effects on fetal thymocyte populations and postnatal T-cell-dependent immune functions after maternal exposure to 5-fluorouracil during pregnancy in mice.
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5-Fluorouracil (5-FU) is a cytostatic anti-tumor drug which is known to have immunosuppressive activities. To assess the immunotoxic effects of 5-FU on fetal thymocyte populations and immune functions after birth, pregnant C57BL/6 mice were orally administered vehicle or 17 mg/kg/day of 5-FU during gestational days (GD) from 6 to 14. The fetal thymocyte populations were analyzed with flow cytometry (CD4/CD8 double staining), and immune functions (a mixed lymphocyte reaction, in vitro cytotoxic T-cell response, in vitro antibody-forming response) after birth were measured. Fetal thymus weight and thymocyte numbers were decreased by 5-FU administration. The decrease of the thymocytes was due mainly to the decrease of small CD4CD8 double positive (DP) thymocytes. The thymocyte numbers and populations recovered to the normal level 1 week after birth. The mixed lymphocyte response at the 6th week after birth tended to be slightly lower than the control levels, but the cytotoxic T-cell response and the antibody-forming response were the same as the control levels. These results suggest that immune functions might recover after birth, although maternal administration of 5-FU has a suppressive effect on fetal thymocyte maturation. (+info)
Gene expression profile induced by 17alpha-ethynyl estradiol, bisphenol A, and genistein in the developing female reproductive system of the rat.
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Exposure to some compounds with estrogenic activity, during fetal development, has been shown to alter development of reproductive organs, leading to abnormal function and disease either after birth or during adulthood. In order to understand the molecular events associated with the estrogenicity of different chemicals and to determine whether common sets of gene expression changes can be predictive of estrogenic activity, we have used microarray technology to determine the transcriptional program influenced by exposure to this class of compounds during organogenesis and development. Changes in patterns of gene expression were determined in the developing uterus and ovaries of Sprague-Dawley rats on GD 20, exposed to graded dosages (sc) of 17alpha-ethynyl estradiol (EE), genistein, or bisphenol A (BPA) from GD 11 to GD 20. Dose levels were roughly equipotent in estrogenic activity. We compared the transcript profiles between treatment groups and controls, using oligonucleotide arrays to determine the expression level of approximately 7000 rat genes and over 1000 expressed squence tags (ESTs). At the highest tested doses of EE, BPA, or genistein, we determined that less than 2% of the mRNA detected by the array showed a 2-fold or greater change in their expression level (increase or decrease). A dose-dependent analysis of the transcript profile revealed a common set of genes whose expression is significantly and reproducibly modified in the same way by each of the 3 chemicals tested. Additionally, each compound induces changes in the expression of other transcripts that are not in common with the others, which indicated not all compounds with estrogenic activity act alike. The results of this study demonstrate that transplacental exposure to chemicals with estrogenic activity changes the gene expression profile of estrogen-sensitive tissues, and that the analysis of the transcript profile of these tissues could be a valuable approach to determining the estrogenicity of different compounds. (+info)
Proliferation and apoptosis in the developing human neocortex.
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The cell kinetics of the developing central nervous system (CNS) is determined by both proliferation and apoptosis. In the human neocortex at week 6 of gestation, proliferation is confined to the ventricular zone, where mitotic figures and nuclear immunoreactivity for proliferating cell nuclear antigen (PCNA) are detectable. Cell division is symmetric, with both daughter cells reentering mitosis. At week 7, the subventricular zone, a secondary proliferative zone, appears. It mainly gives rise to local circuit neurons and glial cells. Around week 12, the ventricular and subventricular zones are thickest, and the nuclear PCNA label is strongest, indicating that proliferation peaks at this stage. Thereafter, asymmetric division becomes the predominant mode of proliferation, with one daughter cell reentering mitosis and the other one migrating out. Towards late gestation, the ventricular and subventricular zones almost completely disappear and proliferation shifts towards the intermediate and subplate zones, where mainly glial cells are generated. A remnant of the subventricular zone with proliferative activity persists into adulthood. In general, proliferation follows a latero-medial gradient in the neocortex lasting longer in its lateral parts. Apoptotic nuclei have been detected around week 5, occurring in low numbers in the ventricular zone at this stage. Apoptotic cell death increases around midgestation and then spreads throughout all cortical layers, with most dying cells located in the ventricular and subventricular zones. This spatial distribution of apoptosis extends into late gestation. During the early postnatal period, most apoptotic cells are still located in the subcortical layers. During early embryonic development, proliferation and apoptosis are closely related, and are probably regulated by common regulators. In the late fetal and early postnatal periods, when proliferation has considerably declined in all cortical layers, apoptosis may occur in neurons whose sprouting axons do not find their targets. (+info)
Effects of aryl hydrocarbon receptor null mutation and in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on prostate and seminal vesicle development in C57BL/6 mice.
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Experiments were conducted to determine the effects of aryl hydrocarbon receptor (AhR) null mutation and in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, alone and in combination, on prostate and seminal vesicle development in C57BL/6 mice. AhR heterozygous (Ahr+/-) mice were mated, and pregnant females were dosed orally on gestation day 13 with TCDD (5 microg/kg) or vehicle. Pups underwent necropsy on postnatal days (PNDs) 35 and 90. Comparison of vehicle-exposed AhR knockout (AhRKO;Ahr-/-) with wild-type (Ahr+/+) pups revealed that the AhR is necessary for normal dorsolateral prostate, anterior prostate, and seminal vesicle development but apparently not for ventral prostate development. In wild-type mice,in utero and lactational TCDD exposure reduced ventral prostate weight by 79-87% and mRNA expression for its major androgen-dependent secretory protein (MP25) by 99%. Yet high levels of mRNA for a secretory protein normally produced primarily by the lateral prostate (PSP94) were expressed. These effects were predominantly AhR dependent because TCDD had little if any effect in AhRKO mice. TCDD reduced dorsolateral prostate weight in wild-type but not AhRKO mice and had no significant effect on expression of mRNA for PSP94 or for probasin, a major androgen-dependent secretory protein. The PSP94 results suggest that TCDD may have caused a respecification of prostatic gene expression. TCDD reduced anterior prostate weight by more than half, and expression of mRNA for its major androgen-dependent secretory protein (renin-1) was greatly reduced. These effects were AhR dependent. Seminal vesicle weight was reduced by TCDD in wild-type mice but was increased in AhRKO mice on PND 35 and decreased on PND 90 (relative weight only). Androgen receptor mRNA levels were not significantly altered in any prostate lobe, and all organs appeared histologically normal in all groups. Serum testosterone concentrations were unchanged, and modest reductions in serum 5alpha-androstane-3alpha,17beta-diol concentrations could not account for the effects on sex organs. Collectively, these results indicate that the AhR signaling pathway plays a role in normal accessory sex organ development and thatin utero and lactational TCDD exposure disrupts development of these organs via spatially and perhaps temporally specific mechanisms. (+info)
Apoptosis in normal rat embryo tissues during early organogenesis: the possible involvement of Bax and Bcl-2.
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Apoptosis commonly occurs in a variety of developmental processes in mammals. In this study, we investigated the relationship between apoptosis and the expression of both Bax and Bcl-2 during the early organogenesis period (9.5-11.5 days of gestation) of rat embryos. Apoptotic cells detected by the terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) method were extremely abundant in the foregut diverticulum at 9.5 days of gestation, while they largely disappeared at 10.5 and 11.5 days of gestation, although they were detected in newly formed mid- and hindgut diverticulum at these times. Real-time RT-PCR analysis of whole embryos revealed that the expression of bax mRNA was constant at days 9.5 to 11.5, while the expression of bcl-2 mRNA gradually increased. Immunohistochemical studies of Bax and Bcl-2 expression revealed that these apoptotic cells were exactly positive to Bax in mirror sections, while their expression of Bcl-2 was generally too low to be detected. A disappearance of apoptotic cells was associated with strong Bcl-2 expression in the foregut diverticulum at 10.5 and 11.5 days of gestation. It was similarly observed that apoptotic cells detected in the cardiogenic area at 9.5 days of gestation disappeared with the formation of the primitive heart tube--accompanied by a strong expression of both Bcl-2 and Bax--in the developmental process of the primitive heart. Apoptotic cells were also observed in the primitive brain vesicle, optic vesicle, otic vesicle, and thyroid primordium at 10.5 and 11.5 days of gestation during the developmental process, with a strong expression of Bax. These results indicate that the Bax and Bcl-2 may be important in regulating the induction of embryonic cell apoptosis during early organogenesis. (+info)
Molecular dissection of craniofacial development using zebrafish.
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The zebrafish, Danio rerio, is a small, freshwater teleost that only began to be used as a vertebrate genetic model by the late George Streisinger in the early 1980s. The strengths of the zebrafish complement genetic studies in mice and embryological studies in avians. Its advantages include high fecundity, externally fertilized eggs and transparent embryos that can be easily manipulated, inexpensive maintenance, and the fact that large-scale mutagenesis screens can be performed. Here we review studies that have used the zebrafish as a model for craniofacial development. Lineage studies in zebrafish have defined the origins of the cranial skeleton at the single-cell level and followed the morphogenetic behaviors of these cells in skeletal condensations. Furthermore, genes identified by random mutational screening have now revealed genetic pathways controlling patterning of the jaw and other pharyngeal arches, as well as the midline of the skull, that are conserved between fish and humans. We discuss the potential impact of specialized mutagenesis screens and the future applications of this versatile, vertebrate developmental model system in the molecular dissection of craniofacial development. (+info)
Distribution of the titf2/foxe1 gene product is consistent with an important role in the development of foregut endoderm, palate, and hair.
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Titf2/foxe1 is a forkhead domain-containing gene expressed in the foregut, in the thyroid, and in the cranial ectoderm of the developing mouse. Titf2 null mice exhibit cleft palate and either a sublingual or completely absent thyroid gland. In humans, mutations of the gene encoding for thyroid transcription factor-2 (TTF-2) result in the Bamforth syndrome, characterized by thyroid agenesis, cleft palate, spiky hair, and choanal atresia. Here, we report a detailed expression pattern of TTF-2 protein during mouse embryogenesis and show its presence in structures where it has not been described yet. At embryonic day (E) 10.5, TTF-2 is expressed in Rathke's pouch, in thyroid, and in the epithelium of the pharyngeal wall and arches, whereas it is absent in the epithelium of the pharyngeal pouches. According to this expression, at E13.5, TTF-2 is present in endoderm derivatives, such as tongue, palate, epiglottis, pharynx, and oesophagus. Later in embryogenesis, we detect TTF-2 in the choanae and whiskers. This pattern of expression helps to define the complex phenotype displayed by human patients. Finally, we show that TTF-2 is a phosphorylated protein. These results help to characterize the domains of TTF-2 expression, from early embryogenesis throughout organogenesis, providing more detail on the potential role of TTF-2 in the development of endoderm and ectoderm derived structures. (+info)
Survey of fibroblast growth factor expression during chick organogenesis.
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Members of the extensive fibroblast growth factor (FGF) family play many key roles during embryonic development. In later development, during the course of organogenesis, these factors have been shown to direct distinct cellular pathways within the context of a particular organ system. To gain more insight into the processes that these factors may be controlling, we conducted a survey of the expression of known FGF family members in chick embryos at stages 18-25. We show the expression patterns of fgf-2, -3, -4, -8, -10, -12, -13, -14, and -18 in the head, trunk, limbs, heart, and tail of the embryo. (+info)