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We studied the effects of maternal exposure to endotoxin on pregnancy outcome, stimulation of the hypothalamo-hypophyseal-adrenal axes (HHAA) of ewes and their fetuses, and maternal production of tumor necrosis factor alpha (TNF alpha), a central mediator in the pathogenesis of bacterial endotoxemia. Either endotoxin (lipopolysaccharide, LPS) from Salmonella typhimurium or saline was administered to pregnant sheep (n = 10) at 137.6 +/- 3.5 days gestational age by slow i.v. infusion at 1 microgram.kg-1 total dose over a 3-h period. Fetuses of ewes treated with LPS became hypoxemic by 2.5 h after initiation of LPS infusion. Maternal ACTH increased and peaked during LPS administration to levels approximately 10-fold greater in treated than in control ewes. In contrast, fetal ACTH levels were maximum at 6-12 h. Maternal and fetal cortisol levels were significantly different from control levels by 1 and 12 h, respectively. Maternal plasma TNF alpha peaked (6-7-fold over baseline) at 1-2 h after initiation of LPS administration and steadily declined over the following 48 h. Four of 5 treated ewes either delivered or their fetuses died within 28 h. In summary, infusion of LPS caused fetal hypoxemia and stimulated both fetal and maternal HHAA followed by preterm labor by 28 h after infusion in 4 of 5 ewes. Three of the fetuses died in utero. Maternal plasma TNF alpha rose rapidly, but the specific role it may play in initiation of preterm labor remains to be elucidated.