Chemically induced alterations in maternal homeostasis and histology of conceptus: their etiologic significance in rat fetal anomalies.

Possible relationships between maternal acid-base-electrolyte imbalance, histological changes in the maternal/extraembryonic tissues (decidua, placenta, membranes enclosing cavities), and fetal anomalies induced by maternotoxic doses of ethylene glycol, sodium salicylate, and cadmium chloride in rats were investigated. Acid-base-electrolyte, histologic and, teratologic studies were conducted concurrently with, as far as feasible, a similar protocol. Ethylene glycol caused 1) maternal homeostatic changes including metabolic acidosis and hyperosmolality, 2) extraembryonic lesions with degeneration of allantois and reduced villigenesis being more prevalent, and 3) materno-fetal effects such as decreases in fetal and maternal body weights, decreased maternal food intake, and fetal abnormalities (vertebral, rib, and sternebral defects). Few of these changes occurred when NaHCO3, an endogenous agent known to correct metabolic acidosis, was coadministered with ethylene glycol. Ethylene glycol-induced maternal metabolic acidosis, concurrent with hyperosmolality, was suspected to contribute toward reduction in villigenesis and fetal anomalies, including body weight reductions. Sodium salicylate induced the following: 1) mild maternal acidosis, hypokalemia, and hypophosphatemia with no significant change in pH; 2) maternal hemorrhage in extraembryonic cavities, papillary proliferation of the visceral yolk sac endoderm, and failure to form the chorioallantoic labyrinth; and 3) resorptions, hydrocephaly, rib defects, and fetal body weight reduction. Upon simultaneous treatment with sodium salicylate, NaHCO3 significantly reduced, and NH4Cl enhanced the incidence of the above histologic and teratologic effects, without significantly altering acid-base values. An etiologic association between the above salicylate-induced maternal and extraembryonic lesions and teratogenicity was likely. Cadmium chloride, whether administered by the intraperitoneal (ip) or intravenous (iv) route, caused 1) hydrocephaly, anophthalmia, vertebral and rib defects, reduction in fetal body weight, resorptions and maternal toxicity (acute peritonitis by the ip route only), and 2) extensive necrosis and hemorrhage in the decidua basalis, hemorrhage in the ectoplacental cone and around Reichert's membrane, and absence of chorioallantoic labyrinth. An etiologic relationship between these teratologic and histologic effects seemed probable, since both were dose-related. From the above studies, it was hypothesized that maternal factors--metabolic acidosis, hyperosmolality, hemorrhages in the ectoplacental cone, extraembryonic cavities, and around Reichert's membrane, and necrosis of decidua basalis--may have, directly or indirectly, reduced fetal nutrition and materno-embryonic gaseous exchange, which ultimately altered fetal development.