Folic acid protects against lipopolysaccharide-induced preterm delivery and intrauterine growth restriction through its anti-inflammatory effect in mice.

Mei Zhao,Hua Wang,Mi-Zhen Xia,De-Xiang Xu,Cheng Zhang,Yuan-Hua Chen,Jun Zhou,Xu-Ting Dong,Xue Chen,Shu-Xian Wu,Ana Claudia Zenclussen

doi:10.1371/journal.pone.0082713

Mei Zhao, Hua Wang + Show 9 more

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https://doi.org/10.1371/journal.pone.0082713

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Journal: PloS one	Publication Date: Dec 6, 2013
Citations: 66	License type: CC BY 4.0

Affiliation: Anhui Medical University

Abstract

Increasing evidence demonstrates that maternal folic acid (FA) supplementation during pregnancy reduces the risk of neural tube defects, but whether FA prevents preterm delivery and intrauterine growth restriction (IUGR) remains obscure. Previous studies showed that maternal lipopolysaccharide (LPS) exposure induces preterm delivery, fetal death and IUGR in rodent animals. The aim of this study was to investigate the effects of FA on LPS-induced preterm delivery, fetal death and IUGR in mice. Some pregnant mice were orally administered with FA (0.6, 3 or 15 mg/kg) 1 h before LPS injection. As expected, a high dose of LPS (300 μg/kg, i.p.) on gestational day 15 (GD15) caused 100% of dams to deliver before GD18 and 89.3% of fetuses dead. A low dose of LPS (75 μg/kg, i.p.) daily from GD15 to GD17 resulted in IUGR. Interestingly, pretreatment with FA prevented LPS-induced preterm delivery and fetal death. In addition, FA significantly attenuated LPS-induced IUGR. Further experiments showed that FA inhibited LPS-induced activation of nuclear factor kappa B (NF-κB) in mouse placentas. Moreover, FA suppressed LPS-induced NF-κB activation in human trophoblast cell line JEG-3. Correspondingly, FA significantly attenuated LPS-induced upregulation of cyclooxygenase (COX)-2 in mouse placentas. In addition, FA significantly reduced the levels of interleukin (IL)-6 and keratinocyte-derived cytokine (KC) in amniotic fluid of LPS-treated mice. Collectively, maternal FA supplementation during pregnancy protects against LPS-induced preterm delivery, fetal death and IUGR through its anti-inflammatory effects.

Highlights

Lipopolysaccharide (LPS) is the major component of the outer membrane of Gram-negative bacteria [1]
Preterm delivery rate dropped to 64.3% when LPS-treated mice were pretreated with high doses of folic acid (FA) (3 or 15 mg/kg), while 71.4% of dams presented preterm delivery when being pretreated with 0.6 mg/kg of FA (Table 1)
The latency interval was 20.5 h (IQR: 16.8-85.8 h) in dams pretreated with 0.6 mg/kg of FA, 22.0 h (IQR: 17.5-86.3 h) in dams pretreated with 3 mg/kg of FA, and 23.5 h (IQR: 18.0-87.3 h) in dams pretreated with 15 mg/kg of FA

Summary

Introduction

Lipopolysaccharide (LPS) is the major component of the outer membrane of Gram-negative bacteria [1]. Humans are constantly exposed to low levels of LPS through bacterial infection. LPS has been detected in the cervical mucus and vaginal fluid from pregnant women with bacterial vaginosis [4]. According to a report from a metaanalysis, bacterial vaginosis doubled the risk of preterm delivery in pregnant women [5]. Microbiological studies suggest that intrauterine infection might account for 25%-40% of preterm delivery [6]. Mimicking maternal infection by exposing pregnant mice to LPS at late gestational stages caused preterm delivery, fetal death and intrauterine growth restriction (IUGR) [7,8,9,10]. Antibiotic therapy is recommended regimen for pregnant women with bacterial infection including bacterial vaginosis [11]. Antibiotics alone might cause impairment on the development of embryos and fetuses [14,15]

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