Introduction of late gestational teratogenesis in rat lung by hypervitaminosis A

Abstract

Long-Evans black-hooded rats treated via stomach tube with 160,000 USP units of retinyl acetate (vitamin A) in 0.5 ml Mazola corn oil on gestational days 15--19 deliver normal-sized litters with significantly decreased viability. Vitamin A is known to effect the differentiation and to stimulate the growth of epithelial cells. Additionally, lung epithelia undergo marked morphologic and physiologic changes late in gestation. Thus the effects of hypervitaminosis A on developing lung constitute an excellent system for the study of teratogenesis late in gestation. Non-hilar, right lower-lobe sections of lungs from the vehicle control and experimental groups, compared via quantitative light microscopy, revealed no significant difference in gross overall histologic appearance on any given day, either in the total number of airways present in the volume of lung sectioned or in the percent area of any individual airway occupied by cells or by lumen. The only significant difference was in the number of cells per square micrometer in that region of an airway occupied by cells. Additionally, there was a significant difference between the control and experimental mitotic indices on gestational days 18 and 19. Thus in the experimental group the number of cells lining the developing airways increases, while the absolute thickness of this cellular layer remains constant. Transmission electron microscopy (TEM) fails to reveal any morphologic differences between control and treated type II pneumatocytes. The increased number of respiratory cells in what otherwise appears to be normal lung may create a diffusion-perfusion imbalance or other difficulties contributing to the heightened neonatal mortality resulting from teratogen exposure late in gestation.

Intralitter variation of neonatal rat lung morphology following prenatal maternal hypervitaminosis A

“…Although the changes associated with vitamin A were similar to younger undisturbed control lungs, delayed maturation does not appear to be related. Fetal studies found no indication of altered timing (Matthews et al, 1981;Armenti and Johnson, 1978) and the lungs of older neonates, 3 to 5 days old, still demonstrated similar thickened septa (110-120 p,m compared to 60-80 pm) . As both the interstitial and epithelial components were thickened, architectural changes may be related to generalized cellular proliferation, fibrosis andlor pulmonary edema.…”

“…Histologically, the lungs typically demonstrate markedly increased septal wall thickness and regional atelectasis. Based on surface tension and electron microscopy studies, development and quantities of surfactant appear to be normal (Armenti and Johnson, 1978;Matthews et al, 1981) and not related to the observed high neonatal mortality following the in utero vitamin A exposure.…”

“…Static lung compliance was also decreased in many animals . Analysis of the functional respiratory epithelium revealed increased mitotic indicies with a hyperplasia in the fetus (Matthews et al, 1981); analysis of the interstitium is underway. Further studies are needed to determine if excessive proliferation continues in the neonatal lung.…”

Postnatal Effects of Prenatal Insult

“…In addition, ultrastructural components normally associated with the synthesis and release of surfactant appear to be within normal limits. (32) In contrast, light microscopy studies, using morphometrics and mitotic indices, have documented the presence of an epithelial hyperplasia.…”

Maternal Serum and Amniotic Fluid Hydroxyproline Levels in Neural Tube Defects

“…Epidemiological studies have suggested that environmental and genetic factors play an important role in the causation of NTD. To date, few specific environmental causes of NTD have been recognized: deficiencies of essential nutrients such as trace elements [1][2][3], vitamin B 12 [4], folic acid [5][6][7] and its derivatives [8][9][10], and excess intake of vitamin A [11]. Decreased antioxidant enzyme levels have also been implicated in the pathophysiology of NTD [12,13].…”