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ToxSci Advance Access published online on September 14, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi300
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Published by Oxford University Press 2005.
Received July 23, 2005
Accepted August 22, 2005

Reproductive and Developmental Toxicology

Effect of N-Acetylcysteine on Lipopolysaccharide-Induced Intra-Uterine Fetal Death and Intra-Uterine Growth Retardation in Mice

De-Xiang Xu 1*, Yuan-Hua Chen 2, Hua Wang 2, Lei Zhao 2, Jian-Ping Wang 2, and Wei Wei 3

1 Department of Toxicology, Anhui Medical University, Hefei, 230032, P. R. China; Key Laboratory of Anti-inflammatory and Immunopharmacology of Anhui Province, Hefei, 230032, P.R.China
2 Department of Toxicology, Anhui Medical University, Hefei, 230032, P. R. China
3 Key Laboratory of Anti-inflammatory and Immunopharmacology of Anhui Province, Hefei, 230032, P.R.China

* To whom correspondence should be addressed.
De-Xiang Xu, E-mail: xudex{at}mail.hf.ah.cn


  Abstract

Lipopolysaccharide (LPS) has been associated with adverse developmental outcome, including embryonic resorption, intra-uterine fetal death (IUFD), intra-uterine growth retardation (IUGR) and preterm delivery. Reactive oxygen species (ROS) have been associated with LPS-induced developmental toxicity. N-acetylcysteine (NAC) is a glutathione (GSH) precursor and direct antioxidant. The present study investigated the effects of NAC on LPS-induced IUFD and IUGR. All pregnant mice except controls were injected with LPS (75 µg/kg, i.p.) on gestational day (gd) 15-17. NAC was administered in two different modes. In mode A, the pregnant mice were pretreated with two doses of NAC (either 50 plus 25 mg/kg or 200 plus 100 mg/kg) before LPS, one (either 50 or 200 mg/kg) at 12 h before LPS and the other (either 25 or 100 mg/kg) at 15 min before LPS. In mode B, the pregnant mice were administered with two doses of NAC (either 50 plus 25 mg/kg or 200 plus 100 mg/kg) in 24 h, one (either 50 or 200 mg/kg) injected immediately after LPS and the other (either 25 or 100 mg/kg) injected 3 h after LPS. 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 measured and skeletal development was evaluated. Results showed that pretreatment with NAC significantly alleviated LPS-induced fetal mortality and reversed LPS-induced growth and skeletal development retardation. Correspondingly, pretreatment with NAC significantly attenuated LPS-induced elevation in TNF-{alpha} concentration in maternal serum and amniotic fluid and lipid peroxidation in maternal and fetal livers. By contrast to pretreatment, posttreatment with NAC had no effect on LPS-induced TNF-{alpha} production and lipid peroxidation. When administered after LPS, NAC did not protect against LPS-induced IUFD and IUGR and in fact aggravated LPS-induced preterm labor. All these results indicate that NAC had a dual effect on LPS-induced IUFD and IUGR. Pretreatment with NAC improves fetal survival and reverses LPS-induced fetal growth and skeletal development retardation, whereas posttreatment with NAC aggravates LPS-induced preterm labor.

Keywords: N-acetylcysteine; lipopolysaccharide; intra-uterine fetal death; intra-uterine growth retardation.
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[Abstract] [Full Text] [PDF]


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