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Altered lysosomal function in the visceral yolk sac can result in abnormal development. As proteolysis is an important function of the rodent visceral yolk sac during early and mid-gestation, we characterized the lysosomal proteolytic enzyme activity of this extraembryonic membrane and determined the effects of inhibitors of protein degradation on embryonic development. Constituent activities of cysteine and aspartic acid proteinases were measured in rat visceral yolk sac on gestation day 12, and the effects of the cysteine proteinase inhibitors leupeptin, E-64 [trans-epoxysuccinyl-l-leucylamido(4-guanido)butane] and N-ethylmaleimide and the aspartic acid proteinase inhibitor pepstatin were determined in Sprague-Dawley rat embryos cultured in vitro from gestation days 10-12. It was determined that only cysteine proteinases, primarily cathepsins B and L, are active in the mid-gestation visceral yolk sac. The cysteine proteinase inhibitors leupeptin and E-64 both produced a concentration-related decrease in embryonic growth, as measured by crown-rump length, somite number, and embryonic protein content, and a concentration-related increase in incidence of abnormalities. A characteristic pattern of abnormalities was produced which involved a decrease in neural tube volume and the formation of a subectodermal blister opposite the point of attachment of the vitelline vessels. At high concentrations, anophthalmia was also observed. The decreased neural tube volume was associated with increased osmolality of the exocoelomic fluid, the major extraembryonic fluid compartment. It is possible that the osmotic change decreased neural tube volume by causing water to move to the compartment with a higher solute concentration, out of the embryo.(ABSTRACT TRUNCATED AT 250 WORDS)

Weanling Charles River CD rats of both sexes were fed 300 mg/kg/day of Piroctone Olamine, an anti-bacterial agent, and were supplemented with 0, 50, 100 or 200 ppm dietary iron as FeSO4.7H2O for six weeks. However, analytical data indicated that Piroctone was degraded in the diet so that the rats received only 225 mg/kg/day. The rats given Piroctone Olamine without iron gained significantly less body weight and ate significantly less feed than controls, with the effect being more pronounced in the males. They also developed severe microcytic, hypochromic anemia. The rats supplemented with all three levels of dietary iron grew at a rate similar to controls. The rats supplemented with 50 ppm dietary iron had anemia with all of the hematological iron-associated factors being significantly depressed. The 100 ppm supplement restored all hematologic factors to normal in the females, but slight reductions remained in the males. The 200 ppm supplement of iron restored all parameters to values similar to the controls in both sexes. These results suggest that the mechanism of the toxicity of Piroctone Olamine is the prevention of dietary iron absorption by in situ chelation.

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