Tumor necrosis factor alpha partially contributes to lipopolysaccharide-induced intra-uterine fetal growth restriction and skeletal development retardation in mice.

Maternal infection is a cause of adverse developmental outcomes. Lipopolysaccharide (LPS)-induced embryonic resorption, intra-uterine fetal death (IUFD) and preterm labor have been well characterized. In the present study, we investigated the effects of maternal LPS exposure on intra-uterine fetal growth and skeletal development. All pregnant mice except controls received an intraperitoneal injection of LPS (75 microg/kg) on gestational days (GD) 15-17. The number of live fetuses, dead fetuses and resorption sites was counted on GD 18. Live fetuses in each litter were weighed. Crown-rump and tail lengths were examined and skeletal development was evaluated. As expected, perinatal LPS exposure resulted in 63.2% fetal death. LPS significantly lowered fetal weight, reduced crown-rump and tail lengths, and retarded skeletal ossification in caudal vertebrae, anterior and posterior phalanges, and supraoccipital bone. Additional experiment showed that a single dose of LPS (75 microg/kg, i.p.) on GD 15 increased the expression of TNF-alpha mRNA in maternal liver and placenta and TNF-alpha concentration in maternal serum and amniotic fluid. Furthermore, pentoxifylline, an inhibitor of TNF-alpha synthesis, significantly inhibited TNF-alpha production, reduced fetal mortality, and reversed LPS-induced fetal intra-uterine growth restriction and skeletal development retardation. Taken together, these results suggest that TNF-alpha is, at least in part, involved in LPS-induced intra-uterine fetal death, intra-uterine growth restriction and skeletal development retardation.