Melatonin protects against lipopolysaccharide‐induced intra‐uterine fetal death and growth retardation in mice

Abstract: Lipopolysaccharide (LPS) has been associated with adverse developmental outcomes, including intra‐uterine fetal death (IUFD) and intra‐uterine growth retardation (IUGR). However, the exact mechanism for LPS‐induced IUFD and IURD remains unclear. LPS stimulates macrophages to generate reactive oxygen species (ROS). Therefore, we hypothesize that ROS may be involved in LPS‐induced IUFD and IURD. Melatonin is a powerful endogenous antioxidant. In this study, we investigated the protective effects of melatonin on LPS‐induced IUFD and IURD in ICR mice. All pregnant mice except controls received an intraperitoneal (75 μ g/kg, i.p.) injection of LPS on gestational day (gd) 15–17. The experiment was carried out in two different modes. In mode A, the pregnant mice received two doses of melatonin within 24 hr, one (5 or 10 mg/kg) injected immediately after LPS and the other (5 or 10 mg/kg) injected at 3 hr after LPS. In mode B, the pregnant mice were pretreated with 10 mg/kg of melatonin 18 hr before LPS and then received two doses of melatonin in 24 hr, one (10 mg/kg) injected immediately after LPS and the other (10 mg/kg) injected 3 hr after LPS. The number of live fetuses, dead fetuses and resorption sites were counted on gd 18. Live fetuses in each litter were weighed. Crown‐rump and tail lengths were examined and skeletal development was evaluated. Results showed that post‐treatments with melatonin significantly attenuated LPS‐induced IUFD in a dose‐dependent manner. Surprisingly, pre‐ plus post‐treatments with melatonin almost blocked LPS‐induced IUFD. In addition, both post‐treatments and pre‐ plus post‐treatments with melatonin significantly alleviated LPS‐induced decreases in crown‐rump and tail lengths and reversed LPS‐induced skeletal developmental retardation. However, melatonin had little effect on LPS‐induced decrease in fetal weight. Furthermore, pre‐ plus post‐treatments with melatonin significantly attenuated LPS‐induced lipid peroxidation in maternal liver. These results indicate that melatonin protects against LPS‐induced IURD and IUGR via counteracting LPS‐induced oxidative stress.