In teratogenic studies toxic effects may manifest themselves in retarded fetal development, such as a reduction in fetal weight. In searching for an additional index, the number of centers of ossification in seven skeletal districts (sternum, metacarpus, metatarsus, cervical and caudal vertebrae, anterior and posterior proximal phalanges) of rat fetuses delivered on days 19, 20 and 21 of gestation were counted and compared. Results showed uneven ossification in day-19 and -20 fetuses, but sufficiently advanced, homogeneous and uniform ossification in day-21 fetuses to provide a reliable quantitative index for evaluating retarded fetal development. It is therefore proposed that the stage of skeletal ossification in day-21 fetuses be used in teratogenic studies in the rat to evaluate retarded fetal development.
Transepithelial pathways of macromolecule transport have been studied in vitro in rabbit nasal respiratory mucosa, maintained at 27 degrees C. Transepithelial electrical potential difference, short-circuit current and resistance were 3.4 +/- 0.5 mV (submucosa positive), 65.0 +/- 6.7 microA cm-2 and 52.1 +/- 5.6 omega cm-2 respectively (n = 15). These electrical characteristics are those of a leaky epithelium allowing macromolecules to permeate paracellularly. A detailed permeation study of a polypeptide (elcatonin, Mw = 3362) was also undertaken. Elcatonin mucosa-submucosa (Jms) and submucosa-mucosa (Jsm) fluxes were measured by radioimmunoassay. With 10 micrograms/ml elcatonin, Jms was significantly larger than Jsm for the whole 120-min period of observation; net flux showed a maximum in the first 30 min (Jms = 13.6 +/- 1.0 ng cm-2 h-1, Jsm = 1.4 +/- 0.1 ng cm-2 h-1, n = 10). Jms fell towards the value of Jsm if the temperature was reduced to 4 degrees C or if the mucosa was simultaneously treated with 0.1 mM dinitrophenol and 3 mM monoiodoacetate. Jms and Jnet followed saturation kinetics with increasing elcatonin concentrations. Adrenocorticotropic hormone (Mr = 4500) produced a similar pattern to elcatonin. However, Jms and Jsm were not significantly different from each other at any time either for [3H]sucrose (Mw = 342) or for [14C]polyethyleneglycol-4000 (Mw = 4000) when present in the bathing medium at 500 microM concentration. The results show active transport of polypeptides in parallel with passive permeation (possibly through leaky intercellular junctions). Active transport does not appear to be related to nonspecific pinocytosis but to receptor-mediated endocytosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration of 5-hydroxytryptamine creatinine sulphate (5-HT) 5-10-20 mg/kg s.c. to pregnant rats during the preimplantation period (1200 h, Days 1 through 5) did not inhibit implantation. Experiment 2: Administration to pregnant rats during the peri-implantation period (0900 h, Day 6) of 5-HT 5 mg/kg s.c. did not affect implantation or embryo-fetal development. 5-HT 10 mg/kg s.c. produced a significant increase (P greater than 0.01) in the resorption rate (31.8%) and severe cardiovascular or ophthalmic malformations in 5.3% of viable fetuses. 5-HT 20 mg/kg produced a resorption rate (97.2%) virtually incompatible with the continuance of pregnancy. Experiment 3: Histological examination of uterine preparations made from Day 6 pregnant rats sacrificed 6, 24, and 30 h after receiving 5-HT 20 mg/kg s.c. showed, in 30 h post-injection preparations, toxic effects at implantation sites (uterine lumen completely deprived of epithelial layer and filled with cellular debris, and complete degeneration of implanted embryos) but no toxic effects between implantation sites. Experiment 4: Administration of 5-HT 10 mg/kg s.c. to pregnant rats during the postimplantation period (Days 10 and 11) produced a 63.2% resorption rate, a reduction in the mean weight of viable fetuses, and severe malformations in 24% of viable fetuses. The embryotoxic activity of 5-HT may be attributed to its vasoconstrictive action which renders the uterine mucosa or trophoblast ischemic, thus causing irreversible damage to the luminal epithelium at the implantation sites.
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