The interrelated objectives of this proposal are 1) to determine if the fetal rat lung is more sensitive than the adult or newborn lung to toxic chemicals; 2) to explore interrelationships between effects of these chemicals as clues to the pathogenesis of organ dysgenesis especially of the lung and vessels; and 3) to determine if certain pulmonary diseases begin with in utero injury by toxic chemicals. To accomplish these objectives, it is proposed to continue defining effects of chemicals which appear to specifically alter growth or assembly of tissues within the lung resulting in models for infantile respiratory distress syndrome, bronchopulmonary dysplasia, bronchiectasis, cystic lung disease and lobar disease and lobar emphysema. (Pregnant women are occupationally exposed to some of these, others are used as drugs.) Chemicals will be given by a suitable route, usually by gavage or intraperitoneally in timed-pregnant rats and after proper doses are found, effects on organogenesis of the lung, vessels and other organs will be appraised by systematic morphological studies and measurements. Agents to be analyzed for effects include 1) copper deficiency (induced nutritionally, by chelating agents and by feeding zinc), 2) cooper excess, 3) vitamin A deficiency and 4) carbon disulfide, 5) polychlorinated biphenyls, 6) paraquat and of urethane. We will study fetuses, litter mate animals at birth, at weaning, at puberty and as adults so that both immediate and latent effects can be detected. Methods include enumeration of pregnancy outcome and systematic gross anatomy, histology, scanning and transmission electron microscopy and some histochemical probes. It is hoped that such studies will lead to early, more reliable ways to detect the potential for lung injury and disease by chemicals. It is also expected that insight will be gained into the pathogenesis of lung, lung-heart-vessel and multiorgan defects which may help to propose which workers, women and men, using such chemicals should be studied epidemiologically to find out whether their progency have congenital malformations due to environmental-occupational chemicals.
