Placental vasoconstriction has been proposed as a primary mechanism for fetal growth retardation. To challenge this hypothesis, we developed a model of fetal growth retardation characterized by increased release of vasodilators: maternal exposure to low dose endotoxin (LPS). This study addressed the hypothesis that LPS administration compromised fetal growth by inducing apoptosis in the utero-placental unit. METHODS: Timed-pregnant dams were randomly assigned to a control or endotoxin treated groups (30μg/kg i.p. daily). At term, fetal and placental weights, immunohistochemical evidence for nitrotyrosine (a marker for peroxynitrite formation) and apoptosis (TUNEL) in the utero-placental unit were determined. Positive TUNEL immunoreactivity results from the incorporation of digoxygenin-labeled UTP to 3′ ends of DNA by the enzyme terminal deoxynucleotide transferase. Multiple 3′ ends is a hallmark of apoptosis. NO release was also determined in explants of uterus and placenta by electrochemistry. RESULTS: Endotoxin administration resulted in growth retardation of both the fetus and placenta. NO release from explants was increased in placenta (6-fold) and uterus (21-fold) in response to LPS. Nitrotyrosine and DNA fragmentation(TUNEL) were absent in control animals but marked in placenta and uterus following endotoxin administration. CONCLUSIONS: Maternal exposure to LPS results in fetal growth retardation. Fetal growth retardation may occur independent of placental vascular insufficiency but in response to DNA damage induced by free radicals and oxidants (possibly peroxynitrite) leading to apoptosis and a net reductin in fetal and placental growth.