Abstract
Lipopolysaccharide (LPS) has been associated with adverse pregnant outcomes, including fetal demise, intra-uterine growth restriction (IUGR), neural tube defects (NTDs) and preterm delivery in rodent animals. Previous studies demonstrated that melatonin protected against LPS-induced fetal demise, IUGR and preterm delivery. The aim of the present study was to investigate the effects of melatonin on LPS-induced NTDs. All pregnant mice except controls were intraperitoneally injected with LPS (25 µg/kg) daily from gestational day (GD)8 to GD12. Some pregnant mice were orally administered with melatonin (MT, 50 mg/kg) before each LPS injection. A five-day LPS injection resulted in 27.5% of fetuses with anencephaly, exencephaly or encephalomeningocele. Additional experiment showed that maternal LPS exposure significantly down-regulated placental proton-coupled folate transporter (pcft) and disturbed folate transport from maternal circulation through the placentas into the fetus. Interestingly, melatonin significantly attenuated LPS-induced down-regulation of placental pcft. Moreover, melatonin markedly improved the transport of folate from maternal circulation through the placentas into the fetus. Correspondingly, orally administered melatonin reduced the incidence of LPS-induced anencephaly, exencephaly or encephalomeningocele. Taken together, these results suggest that orally administered melatonin prevents LPS-induced NTDs through alleviating LPS-induced disturbance of folate transport from maternal circulation through the placenta into the fetus.
Highlights
Lipopolysaccharide (LPS) is a toxic component of cell walls in gram-negative bacteria and is widely present in the digestive tracts of humans and animals [1]
We and others showed that mice exposed to LPS at late gestational stage resulted in fetal demise, intra-uterine growth restriction (IUGR), skeletal development retardation, and preterm delivery [4,5,6,7,8]
A recent study showed that subcutaneous implantation with melatonin protected against LPS-induced preterm delivery [25]
Summary
Lipopolysaccharide (LPS) is a toxic component of cell walls in gram-negative bacteria and is widely present in the digestive tracts of humans and animals [1]. Humans are constantly exposed to a low concentration of LPS through infection. According to an earlier report, mice exposed to LPS at early gestational stage caused embryonic resorption [3]. We and others showed that mice exposed to LPS at late gestational stage resulted in fetal demise, intra-uterine growth restriction (IUGR), skeletal development retardation, and preterm delivery [4,5,6,7,8]. We found that mice exposed to LPS at middle gestational stage caused neural tube defects (NTDs) [9, 10]
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