Effect of N-acetylcysteine on lipopolysaccharide-induced intra-uterine fetal death and intra-uterine growth retardation in mice.
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 microg/kg, ip) 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.
Xu
De-Xiang
DX
Department of Toxicology, Anhui Medical University, Hefei, PR China. xudex@mail.hf.ah.cn
Chen
Yuan-Hua
YH
Wang
Hua
H
Zhao
Lei
L
Wang
Jian-Ping
JP
Wei
Wei
W
D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001846:Bone Development / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000196:embryology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005313:Fetal Death / Q000139:chemically induced / Q000517:prevention & control*; D047109:Fetal Development / Q000187:drug effects*; D005317:Fetal Growth Retardation / Q000139:chemically induced / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D018811:Maternal Exposure; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy
D008070:Lipopolysaccharides; D000111:Acetylcysteine