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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Pediatric surgery international 11 (1996), S. 261-265 
    ISSN: 1437-9813
    Keywords: Testicle ; Maldescent ; Nitrofen ; Germ cell ; Sertoli cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the rat model of nitrofen-induced congenital diaphragmatic hernia, we found the testicles in a high abdominal position in many male animals, and undertook to investigate whether the teratogen interferes with testicular descent and development. Male fetuses from time-mated Wistar rats treated intragastrically with 100 mg nitrofen dissolved in oil on day 9.5 of gestation were compared with control fetuses from mothers receiving only vehicle. The litters were recovered by cesarean section on days 17, 19, and 21 of gestation; the position of the testicles in male animals was recorded, and their volume was measured prior to histological assessment of mean tubular diameter, number of germ cells per tubule, and degree of collagenization of the tunica albuginea. Testicular maldescent was present in 100% of nitrofen-exposed fetuses on the 17th gestational day, 77% of those recovered on day 19, and 41% of those near term (21st day), whereas all control animals but 1 had “descended” gonads on all three days. Testicular volume was significantly decreased in treated fetuses on the 21st gestational day, and the mean tubular diameter was significantly decreased in all three age groups. Experimental and control animals had similar numbers of germ cells per tubule. The albuginea layer had apparently normal collagen content in all groups. These findings suggest that prenatal exposure to nitrofen interferes with both transabdominal descent of the testicle (transinguinal descent is postnatal in the rodent) and its normal development. Previous evidence and the present results authorize speculation on the possible role of nitrofen-induced prenatal thyroid hypofunction in the pathogenesis of maldescent and maldevelopment in this model, since thyroid hormones act directly on Sertoli cells, which secrete müllerian inhibiting substance, which is likely responsible for transabdominal descent.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1437-9813
    Keywords: Esophageal atresia ; Tracheoesophageal fistula ; Esophagus ; Rats ; Adriamycin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We recently reported on a new fetal rat model of esophageal atresia (EA) with tracheoesophageal fistula (TEF) induced by prenatal exposure to adriamycin (1.75 mg/kg i. p. injected daily to the pregnant dam from the 6th to 9th gestational days). With this treatment regime, many fetuses were resorbed and the number of associated malformations was very high. The present study demonstrates that similar doses of the drug administered only on the 8th and 9th gestational days allow higher fetal survival (9.7 ∓ 3.9 vs. 6.8 ∓ 4.7 fetuses per litter, P 〈 0.01) with a similar incidence of EA-TEF (41.2% vs. 56.4%, n. s.) and decreased occurence of associated anorectal and genitourinary malformations. Since this model is an instrument for further investigation of the disturbed cellular and morphogenetic events leading to EA and TEF, the narrowing of the embryologic window obtained by the present study will allow better focusing of the research on the critical period of time involved.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Pediatric surgery international 15 (1999), S. 201-205 
    ISSN: 1437-9813
    Keywords: Key words Esophagus ; Atresia ; Notochord ; Adriamycin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Esophageal atresia (EA) is often accompanied by vertebral defects and other anomalies. The adriamycin rat model of EA has disclosed the embryology of the malformation and shown that the vertebrae and notochord are also abnormal. This study describes the nature of notochord malformations in rat embryos exposed to adriamycin. Time-mated rats received either 1.75 mg/kg adriamycin or vehicle i.p. on gestational days (E) 6 to 9; E-12, E-12.5, and E-13 embryos were harvested, embedded in paraffin, and serially sectioned at 3 μm in transverse plane from the head to the stomach for subsequent PAS staining. The findings in both groups were compared at the three endpoints. Control embryos had neither tracheoesophageal nor notochord malformations. On day 12, only 11/36 adriamycin embryos were normal; 7/36 had abnormal notochords, 11/36 had EA, and 7/36 had both. The corresponding figures for 12.5 days were 12/27, 0/27, 7/27, and 8/27 and those for the day 13 7/23, 5/23, 3/23, and 8/23. The malformed notochords were thickened, bifurcated, or trifurcated in the sagittal plane. The simultaneous presence of notochord and esophageal malformations suggests a direct link between both defects, but our observation of isolated occurrence of both shows that they reflect two expressions of the profound disturbance of embryonic para-axial organization responsible for the cluster of malformations rather than a cause-effect association.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Pediatric surgery international 15 (1999), S. 184-187 
    ISSN: 1437-9813
    Keywords: Key words Congenital diaphragmatic hernia ; Associated malformations ; Nitrofen ; Tracheobronchial anomalies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Neonates with congenital diaphragmatic hernia (CDH) have other malformations that contribute to the high mortality. The nitrofen rat model allows experimental study of these anomalies. This study examines whether the tracheobronchial tree is also abnormal in this model. Time-mated rats received 100 mg nitrofen on gestational day 9.5; 90 fetuses were harvested on day 21 (near full term) and dissected. The trachea and bronchi were stained with alcian blue-alizarin red and their anatomy was examined by transillumination under a microscope. The findings were compared with those of 11 suitable controls. Control pups had no malformations. Those with CDH (n = 57) had significantly decreased numbers of tracheal rings in comparison with controls (22.9 ± 1.9 vs 26 ± 1.9, P 〈 0.05) and 40/57 had fragmented rings (0 in controls). Twelve CDH animals had, in addition, tracheal stenoses of variable severity, sometimes related to vascular rings. Nitrofen fetuses without CDH (n = 33) had only short tracheas and 4 had mild stenoses. Nitrofen-exposed fetuses have, in addition to lung hypoplasia and sometimes CDH, severe tracheobronchial anomalies that suggest the involvement of pathogenetic mechansims capable of acting on various tissue components. The genetic control of organogenesis is most probably disturbed by the teratogen.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1437-9813
    Keywords: Key words Congenital diaphragmatic hernia ; Lung hypoplasia ; Nitrofen ; Thyroid transcription factor 1 ; Hepatocyte nuclear factor 3
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Prenatal exposure to nitrofen induces lung hypoplasia and diaphragmatic hernias very similar to those in human disease, but the mechanisms are still unknown. Thyroid transcription factor 1 (TTF-1) is involved in lung ontogeny and regulation of the expression of surfactant proteins, and is likely abnormally expressed in nitrofen-induced lung hypoplasia. This study examines the effect of nitrofen on TTF-1 messenger RNA (mRNA) expression in the lungs of prenatal rat fetuses and a human lung-cell line (NCI-H441) that expresses both TTF-1 and surfactant proteins in vivo. Lungs from preterm fetuses harvested from rats with 100 mg nitrofen on gestational day 9.5 and NCI-H441 cells maintained in RPMI medium containing 10% fetal bovine serum and exposed to nitrofen for different times and concentrations were assayed for TTF-1 mRNA by northern blot analysis. mRNA for TTF-1 was decreased in nitrofen-exposed pups in comparison with controls, and exposure to nitrofen caused a dose- and time-related decrease in TTF-1 expression in H441 cell cultures. These results indicate that nitrofen downregulates TTF-1 both in vivo and in vitro. Since this interferes with lung development, it is reasonable to accept that lung hypoplasia in this model is in part due to the direct effect of the teratogen rather than to compression by the abdominal viscera herniated into the thorax. This mechanism should be explored in the clinical setting.
    Type of Medium: Electronic Resource
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