ABSTRACT. Prenatal dexamethasone (DEX) treatment is known to accelerate the maturation of both the surfactant system and the fetal lung antioxidant enzyme (AOE) system (Frank L, Lewis P, Sosenko IRS: Pediatrics 75: [569][570][571][572][573][574] 1985). Because of this stimulatory effect of prenatal DEX on the normal late gestational development of the AOE system, we questioned whether this treatment might have a salutary effect on the ability of the newborn rat to tolerate early and prolonged exposure to hyperoxia, inasmuch as the AOE are the primary lung defensive system against high O 2 challenge. In nine experiments with term newborn rats in >95% O 2 , the composite percentage of survival was significantly greater in the prenatal DEX pups at all time periods in hyperoxia from 7 d [control pups, 67 of 94 (71%); prenatal DEX, 96 of 99 (97%») to 14 d [controls, 10 of 32 (31%); prenatal DEX, 18 of 33 (55%») (p < 0.01). In addition to survival per se, the prenatal DEX pups showed significantly decreased lung wet weight/dry weight ratios, pathologic evidence of pulmonary edema, and lung conjugated dienes versus the O2 control newborn group. Of the many comparative parameters examined, the major difference found between the two groups was in the pulmonary AOE responses to hyperoxia. By 2 d in hyperoxia, the prenatal DEX rat pups showed significantly elevated superoxide dismutase, catalase, and glutathione peroxidase activities compared to air control pups, and at 4 and 7 d in O 2 the AOE levels were consistently greater in the DEX group than the AOE responses in the control O2 pups. The more rapid and more pronounced AOE response to hyperoxic challenge may help to explain the substantial protective effect of prenatal DEX versus newborn O 2 toxicity. immature infant. Administration of a long-acting glucocorticoid for 48 h before premature delivery may successfully stimulate surfactant production/secretion in the immature fetal lung and lessen the chance of serious respiratory distress syndrome in the prematurely delivered newborn (1).Previous work from our laboratories has demonstrated that the prenatal administration of DEX to pregnant rats will not only accelerate the late gestational development of the surfactant system in the rat fetuses, but will also accelerate the normal late gestational development of the fetal lung AOE system (2). The late gestational rise in fetal lung SOD, CAT, and GP activities, now demonstrated to be a natural maturational occurrence in five animal species (rat, mouse, rabbit, hamster, and sheep) (3-8), is proposed to be the biochemical means by which the lung is prepared for its safe transition from the quite hypoxic in utero environment to the relatively Os-rich ex utero environment it will encounter immediately at birth (3-5, 9).Because of its marked stimulatory effect on fetal lung AOE system development, we wondered if prenatal DEX treatment might also have a salutary effect on the ability of the newborn animal to tolerate early and prolonged exposure to hyperoxia. We describe herei...