妊娠晚期接触细菌脂多糖对胎儿宫内生长发育和骨骼发育的影响
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摘要
细菌脂多糖(lipopolysaccharide, LPS),又称细菌内毒素(endotoxin, ET),是革兰氏阴性细菌细胞壁结构中的类脂多糖,广泛存在人和动物的消化道内。在肠道感染、饮酒等应激状态下,肠粘膜通透性增加,肠道LPS进入血液循环,引起血液LPS浓度迅速升高。动物实验研究已证实,妊娠早期接触LPS可产生显著的胚胎毒性,主要表现为胚胎吸收、流产和早产,但其作用机制目前尚不清楚。本课题在建立小鼠妊娠晚期接触低剂量LPS引起宫内胎儿死亡(IUFD)、生长发育迟缓(IUGR)和骨骼发育迟缓的动物模型基础上,进一步研究了活性氧(ROS)、一氧化氮(NO)和肿瘤坏死因子α(TNF-α)在LPS引起IUFD、IUGR和骨骼发育迟缓中的作用,并深入探讨了抗氧化剂N-乙酰半胱氨酸(NAC)、抗坏血酸(AA)和褪黑素(MT)对LPS引起IUFD、IUGR和骨骼发育迟缓的影响。
1. LPS诱发IUFD、IUGR和骨骼发育迟缓
为研究LPS诱发IUFD、IUGR和骨骼发育迟缓的作用,LPS各剂量组孕鼠于妊娠第15-17天每天经腹腔注射一定剂量的LPS(25~75μg/kg, ip),对照组经腹腔注射等容量的生理盐水。妊娠第18天处死所有孕鼠,统计活胎、死胎和吸收胎数,称量活胎体重,测量胎鼠身长和尾长,并对胎鼠骨骼发育情况进行评价。结果显示:LPS各剂量组平均每窝死胎数显著高于对照组,并呈明显的剂量-效应关系。进一步观察发现,妊娠晚期接触LPS显著降低活胎平均体重、身长和尾长,并延缓胎鼠枕骨、胸骨、尾椎骨、前指骨和后掌(趾)骨骨化。上述研究结果表明:母鼠妊娠晚期接触低剂量LPS引起IUFD、IUGR和骨骼发育迟缓。
2. TNF-α在LPS引起IUFD、IUGR和骨骼发育迟缓中的作用
为探讨TNF-α在LPS引起IUFD、IUGR和骨骼发育迟缓中的作用,LPS处理组孕鼠于妊娠晚期经腹腔注射LPS(75μg/kg, ip);LPS+PTX处理组孕鼠于注射LPS前0.5 h给予TNF-α的合成抑制剂己酮可可碱(PTX, 100 mg/kg, ip),对照组经腹腔注射等容量的生理盐水或PTX。部分孕鼠给药第1天处死,测母肝、胎肝和胎盘的TNF-αmRNA及羊水和母血清TNF-α水平等。部分孕鼠边续给药3天,于妊娠第18天处死,记录活胎、死胎和吸收胎数,称活胎体重,测量胎鼠身长和尾长,并评价胎鼠骨骼发育情况。结果显示:LPS显著诱导母肝和胎盘组织TNF-αmRNA表达,增加母鼠血清和羊水TNF-α浓度;PTX预处理显著抑制TNF-α产生。进一步研究发现:单纯LPS处理组平均每窝死胎数显著高于对照组,PTX预处理预防LPS引起的IUFD;单纯LPS处理显著降低活胎体重、身长、尾长,延缓胎鼠枕骨、胸骨、尾椎骨、前指骨和后掌(趾)骨骨化,PTX预处理明显减轻LPS引起的生长发育和骨骼发育迟缓。这些研究结果提示:TNF-α至少部分参与LPS引起IUFD、IUGR和骨骼发育迟缓。
3. ROS和NO在LPS引起IUFD、IUGR和骨骼发育迟缓中的作用
为探讨ROS和NO在LPS引起IUFD、IUGR和骨骼发育迟缓中的作用,LPS处理组孕鼠于妊娠第15-17天每天注射LPS(75μg/kg, ip),LPS+PBN处理组孕鼠于注射LPS(75μg/kg, ip)前0.5 h和后3 h分别给予一定剂量的2-苯叔丁基硝酮(PBN, 100+50 mg/kg, ip);LPS+AG处理组孕鼠于注射LPS(75μg/kg, ip)前0.5 h和后3 h分别给予一定剂量的氨基胍(AG, 50+25 mg/kg, ip);对照组给予等容量的生理盐水或AG。部分孕鼠给药第1天处死,测母肝、胎肝和胎盘的MDA等。部分孕鼠边续给药3天,于妊娠第18天处死,记录活胎、死胎和吸收胎数,称量活胎体重,测量胎鼠身长和尾长,并对胎鼠骨骼发育情况进行评价。结果显示:AG处理对LPS引起IUFD、IUGR和骨骼发育迟缓几无影响,而PBN处理组平均每窝死胎数明显低于单纯LPS处理组,PBN处理显著减弱LPS降低胎鼠体重、身长和尾长,并显著抑制LPS引起枕骨、胸骨、尾椎骨、前指骨和后掌(趾)骨骨化不全。进一步研究发现,单纯LPS处理组与对照组比较,母鼠血清和羊水中NO水平无显著性差异(资料未列出);PBN显著对抗LPS引起的氧化应激,主要表现为:母肝、胎肝和胎盘组织MDA水平下降且GSH含量上升。这些研究结果提示:ROS在LPS引起IUFD、IUGR和骨骼发育迟缓中可能发挥重要作用,NO在LPS引起IUFD、IUGR和骨骼发育迟缓中的作用不明显。
4. NAC、AA和MT对LPS引起IUFD、IUGR和骨骼发育迟缓的影响
NAC、AA和MT是重要的抗氧化剂,为探讨NAC、AA和MT对LPS引起IUFD、IUGR和骨骼发育迟缓的影响,孕鼠被分成两个实验组:实验1,LPS处理组孕鼠于妊娠第15-17天每天经腹腔注射LPS(75μg/kg, ip);LPS+NAC组在LPS处理前和/或处理后经腹腔注射NAC;LPS+AA组在LPS处理前和/或处理后经腹腔注射AA;LPS+MT组在LPS处理前和/或处理后经腹腔注射MT,对照组给予等容量的生理盐水或NAC、AA和MT。所有孕鼠于妊娠第18天处死,统计活胎、死胎和吸收胎数,称量活胎体重,测量活胎身长和尾长,并评价胎鼠骨骼发育情况。实验2,LPS处理组孕鼠于妊娠第15天经腹腔注射单剂量的LPS(75μg/kg),LPS+NAC、LPS+AA和LPS+MT组孕鼠于LPS处理前和/或处理后经腹腔分别注射注射NAC、AA和MT,对照组给予等容量的生理盐水或NAC、AA和MT。孕鼠于LPS处理后1.5 h或6 h处死,检测母肝、胎肝和胎盘组织丙二醛(MDA)和谷胱甘肽(GSH)水平,并测LPS+NAC组羊水和血清TNF-α含量。结果显示:LPS+NAC预处理组、LPS+AA预处理组、LPS+MT预+后处理组和后处理组宫内胎儿死亡数显著低于单纯LPS处理组;LPS+NAC后处理、LPS+AA后和预+后处理组平均每窝死胎数与单纯LPS组比较差异无显著性意义。此外,LPS+NAC预处理和后处理、LPS+AA各处理和LPS+MT各处理组均显著抑制LPS引起IUGR和骨骼发育迟缓。进一步研究发现:NAC预处理显著抑制LPS引起母肝、胎肝和胎盘组织脂质过氧化,NAC后处理显著抑制LPS引起母肝组织脂质过氧化,但对LPS引起的胎肝和胎盘组织脂质过氧化无明显抑制作用;NAC预处理显著抑制LPS引起血清和羊水TNF-α水平上升,而NAC后处理对LPS引起血清TNF-α水平上升无明显影响。AA预和后处理均显著抑制LPS引起母肝、胎肝和胎盘组织脂质过氧化,但AA预处理的作用强于后处理。MT预+后处理显著抑制LPS引起母肝和胎盘组织脂质过氧化,MT后处理显著抑制LPS引起胎盘组织脂质过氧化;但MT预+后处理和后处理对LPS降低母肝组织GSH含量均无明显影响。上述研究结果提示:NAC预处理预防LPS引起IUFD、IUGR和骨骼发育迟缓,NAC后处理对LPS引起IUFD无明显影响,且加重LPS引起早产;AA预处理通过抑制LPS引起的氧化应激,预防LPS引起IUFD、IUGR和骨骼发育迟缓,AA后和预+后处理对抗LPS引起IUGR和骨骼发育迟缓,但对LPS引起IUFD无保护作用;MT通过抑制LPS引起氧化应激,对抗LPS引起IUFD、IUGR和骨骼发育迟缓。
根据上述研究结果,本课题可得出如下结论:(1)母鼠妊娠晚期接触LPS引起IUFD、IUGR和骨骼发育迟缓;(2)TNF-α部分参与了LPS引起IUFD、IUGR和骨骼发育迟缓;(3)ROS在LPS引起IUFD、IUGR和骨骼发育迟缓中发挥重要作用;NO在LPS引起IUFD、IUGR和骨骼发育迟缓中的作用不明显;(4)NAC预处理预防LPS引起IUFD、IUGR和骨骼发育迟缓,NAC后处理对LPS引起IUFD无明显影响,且加重LPS引起早产;AA预处理预防LPS引起IUFD、IUGR和骨骼发育迟缓,AA后和预+后处理对抗LPS引起IUGR和骨骼发育迟缓,但对LPS引起IUFD无保护作用;MT对LPS引起IUFD、IUGR和骨骼发育迟缓具有明显保护作用。
Lipopolysaccharide (LPS) or endotoxin (ET) is a toxic component of cell walls of gram-negative bacteria and is widely present in the digestive tracts of humans and animals. Gastrointestinal distress and alcohol drinking often increase permeability of LPS from gastrointestinal tract into blood. LPS has been associated with adverse developmental outcome, including embryonic resorption, abortion and preterm labor in animals. However, the exact mechanism of LPS-induced developmental toxicity remains unclear. In this study, we investigated the effect of prenatal exposure to lipopolysaccharide on intra-uterine fetal growth development and skeletal development in mice. We also explored the roles of reactive oxygen species (ROS), tumor necrosis factor-α(TNF-α) and nitric oxide (NO) on LPS-induced IUFD, IUGR and skeletal development retardation in mice, and the effect of N-acetylcysteine (NAC), ascorbic acid (AA) and melatonin (N-acetyl-5-methoxytryptamine, MT) on LPS induced IUFD, IUGR and skeletal development retardation.
1. The effect of prenatal exposure to lipopolysaccharide on intra-uterine fetal growth development and skeletal development in mice
To investigate the effects of LPS on IUFD, IUGR and skeletal development retardation. The timed pregnant mice were injected with different doses of LPS (25~75μg/kg, ip) on gestational day (gd) 15-17. 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 examined and skeletal development was evaluated. Results showed that maternally administered LPS significantly increased fetal mortality in a dose-dependent manner. In addition, maternally administered LPS significantly reduced fetal weight and crown-rump and tail lengths of live fetuses and retarded skeletal ossification in caudal vertebrae, anterior and posterior phalanges, and supraoccipital bone in a dose-dependent manner. These results indicate that maternal LPS exposure at late gestational stages results in IUFD, IUGR and skeletal development retardation in mice.
2. The role of TNF-αin LPS-induced IUFD, IUGR and skeletal development retardation in mice
In this study, we investigated the role of TNF-αon LPS-induced IUFD, IUGR and skeletal development retardation in mice. All pregnant mice except controls accepted an intraperitoneal injection of LPS (75μg/kg, ip) daily on gestational late stage. In LPS+PTX group, the pregnant mice were injected with pentoxifylline (PTX, 100 mg/kg, ip) at 0.5 h before LPS treatment. The saline- and PTX- treated pregnant mice served as controls. Some pregnant mice were sacrificed on the day of injection, maternal liver and fetal liver and placenta were dissected for total RNA extraction, maternal serum and amniotic fluid were collected for measurement of TNF-αconcentration, and the left were injected the drug continuously and killed on gd 18. The number of live fetuses, dead fetuses and resorption sites were counted in each litter. Live fetuses were weighted, Crown-rump and tail lengths were measured, and the skeleton of live fetuses were evaluated in each litter. Results showed that pretreatment with PTX, an inhibitor of TNF-αsynthesis, was used to inhibit LPS-evoked TNF-αproduction, As expected, almost blocked LPS-induced IUFD. In addition, PTX significantly alleviated LPS-induced decreases in crown-rump and tail lengths and decrease in fetal weight, and reversed LPS-induced developmental retardation in Posterior phalanx, Caudal vertebrae and breastbone. PTX significantly attenuated LPS-induced lipid peroxidation in maternal liver, fetal liver and placenta. However, PTX had not effect on LPS-induced GSH depletion in maternal liver. Furthermore, PTX evidently mitigated LPS-induced increase in TNF-αconcentration in amniotic fluid and maternal serum. These results indicate that TNF-αis, at least in part, mediated in LPS-induced IUFD, IUGR and skeletal development retardation in mice.
3. The roles of ROS and NO in LPS-induced IUFD, IUGR and skeletal development retardation in mice
To investigated the role of Reactive oxygen species (ROS) and nitric oxide (NO) on LPS-induced IUFD, IUGR and skeletal development retardation in mice. In LPS-treated group, the pregnant mice were injected with LPS (75μg/kg, ip) daily on gestational late stage. In the LPS+PBN group, the pregnant mice were injected with 100 mg/kg of Alpha-phenyl-N-t-butylnitrone (PBN, ip) at 0.5 h before LPS (75μg/kg, ip) treatment, followed by additional dose (50 mg/kg) of PBN at 3 h after LPS treatment. In the LPS+AG group, the pregnant mice were injected with 50 mg/kg of aminoguanidine (AG, ip) at 0.5 h before LPS (75μg/kg, ip) treatment, followed by additional dose (25 mg/kg) of AG at 3 h after LPS treatment. the saline- and AG- treated pregnant mice served as controls. Some pregnant mice were sacrificed on the day of injection, maternal liver, fetal liver and placenta were dissected for measurement of MDA concentration and so on. The left were injected the drug continuously and killed on gd 18, For each litter, the number of live fetuses, dead fetuses and resorption sites were counted. Live fetuses in each litter were weighted. Crown-rump and tail lengths were measured. And the skeleton of all live fetuses in each litter were evaluated. Results showed that PBN, a free radical spin-trapping agent, almost blocked LPS-induced IUFD and revered LPS-induced intra-uterine skeletal development retardation. And abolished LPS-induced decrease in fetal weight and crown-rump and tail lengths. However, AG, an inhibitor of inducible nitric oxide synthase (iNOS) activity, which was used to inhibit LPS-evoked NO production, had no effect on LPS-induced IUFD, IUGR and skeletal development retardation in mice. Furthermore, PBN significantly attenuated LPS-induced lipid peroxidation in maternal liver, fetal liver and placenta, and GSH depletion in maternal liver and fetal liver. In addition, NO contents in serum and amniotic fluid were statistically indistinguishable between LPS-treated groups and control (data not shown). These results suggest that oxidative stress is, at least in part, mediated in LPS-induced IUFD, IUGR and skeletal development retardation; and LPS-induced IUFD, IUGR and skeletal development retardation in mice are independent of NO production.
4. The effect of NAC, AA and MT on LPS-induced IUFD, IUGR and skeletal development retardation in mice
NAC, AA and MT are potent antioxidants. To investigate the role of NAC, AA and MT on LPS-induced IUFD, IUGR and skeletal development retardation in ICR mice. The present study included two separate experiments. In experiment one, All pregnant mice except controls (either saline or NAC, AA, MT) received an intraperitoneal injection of LPS (75μg/kg, ip) on gd 15-17. In LPS+NAC, LPS+AA and LPS+MT groups, the pregnant mice were treated with NAC, AA or MT at before and / or 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. In experiment two, All pregnant mice except controls (either saline or NAC, AA, MT) received an intraperitoneal (75μg/kg) injection of LPS on gd 15. In LPS+NAC, LPS+AA and LPS+MT groups, the pregnant mice were treated with NAC, AA or MT at before and / or after LPS. All dams were sacrificed at 1.5 h or 6 h after LPS treatment. Maternal liver, fetal liver and placenta were dissected for GSH and MDA measurements, maternal serum and amniotic fluid were collected for TNF-αanalyses. Results showed that pretreatment with NAC, AA, and pre- plus post- treatments and post-treatment with MT significantly attenuated LPS-induced IUFD. However, post-treatment with NAC, both post- and pre- plus post- treatments with AA had less effect on LPS-induced IUFD. In addition, pre- and post- treatment with NAC, AA- and MT- treatments significantly alleviated LPS-induced IUGR, and reversed LPS-induced skeletal developmental retardation. Furthermore, pretreatment with NAC significantly attenuated LPS-induced elevation in TNF-a concentration in maternal serum and amniotic fluid and lipid peroxidation in maternal liver, fetal livers and placenta. By contrast to pretreatment, post-treatment with NAC had no effect on LPS-induced TNF-a production and lipid peroxidation; Pre- and post- treatmentwith AA significantly attenuated LPS-induced lipid peroxidation; pre- plus post- treatments with melatonin significantly attenuated LPS-induced lipid peroxidation in maternal liver and placenta. However, melatonin had no effect on LPS-induced GSH depletion. These results indicate that NAC had a dual effect on LPS-induced IUFD, IUGR and skeletal development. Pretreatment with NAC improves fetal survival and reverses LPS-induced IUGR and skeletal development retardation, whereas post-treatment with NAC aggravates LPS induced preterm labor; Pretreatment with AA protected against LPS-induced IUFD and reversed LPS-induced IUGR and skeletal development retardation, whereas post-treatment and pre- + post-treatment had less effect on LPS-induced IUFD. MT protects against LPS-induced IURD, IUGR and skeletal development retardation via counteracting LPS-induced oxidative stress.
In summary, the present results allow us to reach the following conclusions. First, the timed pregnant mice were injected low dose of LPS on gestational day (gd) 15-17 resulted in intra-uterine fetal death (IUFD), intra-uterine growth retardation (IUGR) and skeletal development retardation in mice; second, TNF-αpartially contributes to LPS-induced IUFD, IUGR and skeletal development retardation in mice; third, LPS-induced IUFD, IUGR and skeletal development retardation in mice is mediated, at least in part, by reactive oxygen species; fourth, LPS-induced IURD, IUGR and skeletal development retardation in mice is independent of NO production; and fifth, NAC had a dual effect on LPS-induced IUFD, IUGR and skeletal development retardation, pretreatment with NAC improves fetal survival and reverses LPS-induced IUGR and skeletal development retardation, whereas post-treatment with NAC aggravates LPS induced preterm labor; Pretreatment with AA protected against LPS-induced IUFD and reversed LPS-induced IUGR and skeletal development retardation, whereas post-treatment and pre- + post-treatment had less effect on LPS-induced IUFD; and MT protects against LPS-induced IURD, IUGR and skeletal development retardation in mice.
1. LPS诱发IUFD、IUGR和骨骼发育迟缓
为研究LPS诱发IUFD、IUGR和骨骼发育迟缓的作用,LPS各剂量组孕鼠于妊娠第15-17天每天经腹腔注射一定剂量的LPS(25~75μg/kg, ip),对照组经腹腔注射等容量的生理盐水。妊娠第18天处死所有孕鼠,统计活胎、死胎和吸收胎数,称量活胎体重,测量胎鼠身长和尾长,并对胎鼠骨骼发育情况进行评价。结果显示:LPS各剂量组平均每窝死胎数显著高于对照组,并呈明显的剂量-效应关系。进一步观察发现,妊娠晚期接触LPS显著降低活胎平均体重、身长和尾长,并延缓胎鼠枕骨、胸骨、尾椎骨、前指骨和后掌(趾)骨骨化。上述研究结果表明:母鼠妊娠晚期接触低剂量LPS引起IUFD、IUGR和骨骼发育迟缓。
2. TNF-α在LPS引起IUFD、IUGR和骨骼发育迟缓中的作用
为探讨TNF-α在LPS引起IUFD、IUGR和骨骼发育迟缓中的作用,LPS处理组孕鼠于妊娠晚期经腹腔注射LPS(75μg/kg, ip);LPS+PTX处理组孕鼠于注射LPS前0.5 h给予TNF-α的合成抑制剂己酮可可碱(PTX, 100 mg/kg, ip),对照组经腹腔注射等容量的生理盐水或PTX。部分孕鼠给药第1天处死,测母肝、胎肝和胎盘的TNF-αmRNA及羊水和母血清TNF-α水平等。部分孕鼠边续给药3天,于妊娠第18天处死,记录活胎、死胎和吸收胎数,称活胎体重,测量胎鼠身长和尾长,并评价胎鼠骨骼发育情况。结果显示:LPS显著诱导母肝和胎盘组织TNF-αmRNA表达,增加母鼠血清和羊水TNF-α浓度;PTX预处理显著抑制TNF-α产生。进一步研究发现:单纯LPS处理组平均每窝死胎数显著高于对照组,PTX预处理预防LPS引起的IUFD;单纯LPS处理显著降低活胎体重、身长、尾长,延缓胎鼠枕骨、胸骨、尾椎骨、前指骨和后掌(趾)骨骨化,PTX预处理明显减轻LPS引起的生长发育和骨骼发育迟缓。这些研究结果提示:TNF-α至少部分参与LPS引起IUFD、IUGR和骨骼发育迟缓。
3. ROS和NO在LPS引起IUFD、IUGR和骨骼发育迟缓中的作用
为探讨ROS和NO在LPS引起IUFD、IUGR和骨骼发育迟缓中的作用,LPS处理组孕鼠于妊娠第15-17天每天注射LPS(75μg/kg, ip),LPS+PBN处理组孕鼠于注射LPS(75μg/kg, ip)前0.5 h和后3 h分别给予一定剂量的2-苯叔丁基硝酮(PBN, 100+50 mg/kg, ip);LPS+AG处理组孕鼠于注射LPS(75μg/kg, ip)前0.5 h和后3 h分别给予一定剂量的氨基胍(AG, 50+25 mg/kg, ip);对照组给予等容量的生理盐水或AG。部分孕鼠给药第1天处死,测母肝、胎肝和胎盘的MDA等。部分孕鼠边续给药3天,于妊娠第18天处死,记录活胎、死胎和吸收胎数,称量活胎体重,测量胎鼠身长和尾长,并对胎鼠骨骼发育情况进行评价。结果显示:AG处理对LPS引起IUFD、IUGR和骨骼发育迟缓几无影响,而PBN处理组平均每窝死胎数明显低于单纯LPS处理组,PBN处理显著减弱LPS降低胎鼠体重、身长和尾长,并显著抑制LPS引起枕骨、胸骨、尾椎骨、前指骨和后掌(趾)骨骨化不全。进一步研究发现,单纯LPS处理组与对照组比较,母鼠血清和羊水中NO水平无显著性差异(资料未列出);PBN显著对抗LPS引起的氧化应激,主要表现为:母肝、胎肝和胎盘组织MDA水平下降且GSH含量上升。这些研究结果提示:ROS在LPS引起IUFD、IUGR和骨骼发育迟缓中可能发挥重要作用,NO在LPS引起IUFD、IUGR和骨骼发育迟缓中的作用不明显。
4. NAC、AA和MT对LPS引起IUFD、IUGR和骨骼发育迟缓的影响
NAC、AA和MT是重要的抗氧化剂,为探讨NAC、AA和MT对LPS引起IUFD、IUGR和骨骼发育迟缓的影响,孕鼠被分成两个实验组:实验1,LPS处理组孕鼠于妊娠第15-17天每天经腹腔注射LPS(75μg/kg, ip);LPS+NAC组在LPS处理前和/或处理后经腹腔注射NAC;LPS+AA组在LPS处理前和/或处理后经腹腔注射AA;LPS+MT组在LPS处理前和/或处理后经腹腔注射MT,对照组给予等容量的生理盐水或NAC、AA和MT。所有孕鼠于妊娠第18天处死,统计活胎、死胎和吸收胎数,称量活胎体重,测量活胎身长和尾长,并评价胎鼠骨骼发育情况。实验2,LPS处理组孕鼠于妊娠第15天经腹腔注射单剂量的LPS(75μg/kg),LPS+NAC、LPS+AA和LPS+MT组孕鼠于LPS处理前和/或处理后经腹腔分别注射注射NAC、AA和MT,对照组给予等容量的生理盐水或NAC、AA和MT。孕鼠于LPS处理后1.5 h或6 h处死,检测母肝、胎肝和胎盘组织丙二醛(MDA)和谷胱甘肽(GSH)水平,并测LPS+NAC组羊水和血清TNF-α含量。结果显示:LPS+NAC预处理组、LPS+AA预处理组、LPS+MT预+后处理组和后处理组宫内胎儿死亡数显著低于单纯LPS处理组;LPS+NAC后处理、LPS+AA后和预+后处理组平均每窝死胎数与单纯LPS组比较差异无显著性意义。此外,LPS+NAC预处理和后处理、LPS+AA各处理和LPS+MT各处理组均显著抑制LPS引起IUGR和骨骼发育迟缓。进一步研究发现:NAC预处理显著抑制LPS引起母肝、胎肝和胎盘组织脂质过氧化,NAC后处理显著抑制LPS引起母肝组织脂质过氧化,但对LPS引起的胎肝和胎盘组织脂质过氧化无明显抑制作用;NAC预处理显著抑制LPS引起血清和羊水TNF-α水平上升,而NAC后处理对LPS引起血清TNF-α水平上升无明显影响。AA预和后处理均显著抑制LPS引起母肝、胎肝和胎盘组织脂质过氧化,但AA预处理的作用强于后处理。MT预+后处理显著抑制LPS引起母肝和胎盘组织脂质过氧化,MT后处理显著抑制LPS引起胎盘组织脂质过氧化;但MT预+后处理和后处理对LPS降低母肝组织GSH含量均无明显影响。上述研究结果提示:NAC预处理预防LPS引起IUFD、IUGR和骨骼发育迟缓,NAC后处理对LPS引起IUFD无明显影响,且加重LPS引起早产;AA预处理通过抑制LPS引起的氧化应激,预防LPS引起IUFD、IUGR和骨骼发育迟缓,AA后和预+后处理对抗LPS引起IUGR和骨骼发育迟缓,但对LPS引起IUFD无保护作用;MT通过抑制LPS引起氧化应激,对抗LPS引起IUFD、IUGR和骨骼发育迟缓。
根据上述研究结果,本课题可得出如下结论:(1)母鼠妊娠晚期接触LPS引起IUFD、IUGR和骨骼发育迟缓;(2)TNF-α部分参与了LPS引起IUFD、IUGR和骨骼发育迟缓;(3)ROS在LPS引起IUFD、IUGR和骨骼发育迟缓中发挥重要作用;NO在LPS引起IUFD、IUGR和骨骼发育迟缓中的作用不明显;(4)NAC预处理预防LPS引起IUFD、IUGR和骨骼发育迟缓,NAC后处理对LPS引起IUFD无明显影响,且加重LPS引起早产;AA预处理预防LPS引起IUFD、IUGR和骨骼发育迟缓,AA后和预+后处理对抗LPS引起IUGR和骨骼发育迟缓,但对LPS引起IUFD无保护作用;MT对LPS引起IUFD、IUGR和骨骼发育迟缓具有明显保护作用。
Lipopolysaccharide (LPS) or endotoxin (ET) is a toxic component of cell walls of gram-negative bacteria and is widely present in the digestive tracts of humans and animals. Gastrointestinal distress and alcohol drinking often increase permeability of LPS from gastrointestinal tract into blood. LPS has been associated with adverse developmental outcome, including embryonic resorption, abortion and preterm labor in animals. However, the exact mechanism of LPS-induced developmental toxicity remains unclear. In this study, we investigated the effect of prenatal exposure to lipopolysaccharide on intra-uterine fetal growth development and skeletal development in mice. We also explored the roles of reactive oxygen species (ROS), tumor necrosis factor-α(TNF-α) and nitric oxide (NO) on LPS-induced IUFD, IUGR and skeletal development retardation in mice, and the effect of N-acetylcysteine (NAC), ascorbic acid (AA) and melatonin (N-acetyl-5-methoxytryptamine, MT) on LPS induced IUFD, IUGR and skeletal development retardation.
1. The effect of prenatal exposure to lipopolysaccharide on intra-uterine fetal growth development and skeletal development in mice
To investigate the effects of LPS on IUFD, IUGR and skeletal development retardation. The timed pregnant mice were injected with different doses of LPS (25~75μg/kg, ip) on gestational day (gd) 15-17. 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 examined and skeletal development was evaluated. Results showed that maternally administered LPS significantly increased fetal mortality in a dose-dependent manner. In addition, maternally administered LPS significantly reduced fetal weight and crown-rump and tail lengths of live fetuses and retarded skeletal ossification in caudal vertebrae, anterior and posterior phalanges, and supraoccipital bone in a dose-dependent manner. These results indicate that maternal LPS exposure at late gestational stages results in IUFD, IUGR and skeletal development retardation in mice.
2. The role of TNF-αin LPS-induced IUFD, IUGR and skeletal development retardation in mice
In this study, we investigated the role of TNF-αon LPS-induced IUFD, IUGR and skeletal development retardation in mice. All pregnant mice except controls accepted an intraperitoneal injection of LPS (75μg/kg, ip) daily on gestational late stage. In LPS+PTX group, the pregnant mice were injected with pentoxifylline (PTX, 100 mg/kg, ip) at 0.5 h before LPS treatment. The saline- and PTX- treated pregnant mice served as controls. Some pregnant mice were sacrificed on the day of injection, maternal liver and fetal liver and placenta were dissected for total RNA extraction, maternal serum and amniotic fluid were collected for measurement of TNF-αconcentration, and the left were injected the drug continuously and killed on gd 18. The number of live fetuses, dead fetuses and resorption sites were counted in each litter. Live fetuses were weighted, Crown-rump and tail lengths were measured, and the skeleton of live fetuses were evaluated in each litter. Results showed that pretreatment with PTX, an inhibitor of TNF-αsynthesis, was used to inhibit LPS-evoked TNF-αproduction, As expected, almost blocked LPS-induced IUFD. In addition, PTX significantly alleviated LPS-induced decreases in crown-rump and tail lengths and decrease in fetal weight, and reversed LPS-induced developmental retardation in Posterior phalanx, Caudal vertebrae and breastbone. PTX significantly attenuated LPS-induced lipid peroxidation in maternal liver, fetal liver and placenta. However, PTX had not effect on LPS-induced GSH depletion in maternal liver. Furthermore, PTX evidently mitigated LPS-induced increase in TNF-αconcentration in amniotic fluid and maternal serum. These results indicate that TNF-αis, at least in part, mediated in LPS-induced IUFD, IUGR and skeletal development retardation in mice.
3. The roles of ROS and NO in LPS-induced IUFD, IUGR and skeletal development retardation in mice
To investigated the role of Reactive oxygen species (ROS) and nitric oxide (NO) on LPS-induced IUFD, IUGR and skeletal development retardation in mice. In LPS-treated group, the pregnant mice were injected with LPS (75μg/kg, ip) daily on gestational late stage. In the LPS+PBN group, the pregnant mice were injected with 100 mg/kg of Alpha-phenyl-N-t-butylnitrone (PBN, ip) at 0.5 h before LPS (75μg/kg, ip) treatment, followed by additional dose (50 mg/kg) of PBN at 3 h after LPS treatment. In the LPS+AG group, the pregnant mice were injected with 50 mg/kg of aminoguanidine (AG, ip) at 0.5 h before LPS (75μg/kg, ip) treatment, followed by additional dose (25 mg/kg) of AG at 3 h after LPS treatment. the saline- and AG- treated pregnant mice served as controls. Some pregnant mice were sacrificed on the day of injection, maternal liver, fetal liver and placenta were dissected for measurement of MDA concentration and so on. The left were injected the drug continuously and killed on gd 18, For each litter, the number of live fetuses, dead fetuses and resorption sites were counted. Live fetuses in each litter were weighted. Crown-rump and tail lengths were measured. And the skeleton of all live fetuses in each litter were evaluated. Results showed that PBN, a free radical spin-trapping agent, almost blocked LPS-induced IUFD and revered LPS-induced intra-uterine skeletal development retardation. And abolished LPS-induced decrease in fetal weight and crown-rump and tail lengths. However, AG, an inhibitor of inducible nitric oxide synthase (iNOS) activity, which was used to inhibit LPS-evoked NO production, had no effect on LPS-induced IUFD, IUGR and skeletal development retardation in mice. Furthermore, PBN significantly attenuated LPS-induced lipid peroxidation in maternal liver, fetal liver and placenta, and GSH depletion in maternal liver and fetal liver. In addition, NO contents in serum and amniotic fluid were statistically indistinguishable between LPS-treated groups and control (data not shown). These results suggest that oxidative stress is, at least in part, mediated in LPS-induced IUFD, IUGR and skeletal development retardation; and LPS-induced IUFD, IUGR and skeletal development retardation in mice are independent of NO production.
4. The effect of NAC, AA and MT on LPS-induced IUFD, IUGR and skeletal development retardation in mice
NAC, AA and MT are potent antioxidants. To investigate the role of NAC, AA and MT on LPS-induced IUFD, IUGR and skeletal development retardation in ICR mice. The present study included two separate experiments. In experiment one, All pregnant mice except controls (either saline or NAC, AA, MT) received an intraperitoneal injection of LPS (75μg/kg, ip) on gd 15-17. In LPS+NAC, LPS+AA and LPS+MT groups, the pregnant mice were treated with NAC, AA or MT at before and / or 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. In experiment two, All pregnant mice except controls (either saline or NAC, AA, MT) received an intraperitoneal (75μg/kg) injection of LPS on gd 15. In LPS+NAC, LPS+AA and LPS+MT groups, the pregnant mice were treated with NAC, AA or MT at before and / or after LPS. All dams were sacrificed at 1.5 h or 6 h after LPS treatment. Maternal liver, fetal liver and placenta were dissected for GSH and MDA measurements, maternal serum and amniotic fluid were collected for TNF-αanalyses. Results showed that pretreatment with NAC, AA, and pre- plus post- treatments and post-treatment with MT significantly attenuated LPS-induced IUFD. However, post-treatment with NAC, both post- and pre- plus post- treatments with AA had less effect on LPS-induced IUFD. In addition, pre- and post- treatment with NAC, AA- and MT- treatments significantly alleviated LPS-induced IUGR, and reversed LPS-induced skeletal developmental retardation. Furthermore, pretreatment with NAC significantly attenuated LPS-induced elevation in TNF-a concentration in maternal serum and amniotic fluid and lipid peroxidation in maternal liver, fetal livers and placenta. By contrast to pretreatment, post-treatment with NAC had no effect on LPS-induced TNF-a production and lipid peroxidation; Pre- and post- treatmentwith AA significantly attenuated LPS-induced lipid peroxidation; pre- plus post- treatments with melatonin significantly attenuated LPS-induced lipid peroxidation in maternal liver and placenta. However, melatonin had no effect on LPS-induced GSH depletion. These results indicate that NAC had a dual effect on LPS-induced IUFD, IUGR and skeletal development. Pretreatment with NAC improves fetal survival and reverses LPS-induced IUGR and skeletal development retardation, whereas post-treatment with NAC aggravates LPS induced preterm labor; Pretreatment with AA protected against LPS-induced IUFD and reversed LPS-induced IUGR and skeletal development retardation, whereas post-treatment and pre- + post-treatment had less effect on LPS-induced IUFD. MT protects against LPS-induced IURD, IUGR and skeletal development retardation via counteracting LPS-induced oxidative stress.
In summary, the present results allow us to reach the following conclusions. First, the timed pregnant mice were injected low dose of LPS on gestational day (gd) 15-17 resulted in intra-uterine fetal death (IUFD), intra-uterine growth retardation (IUGR) and skeletal development retardation in mice; second, TNF-αpartially contributes to LPS-induced IUFD, IUGR and skeletal development retardation in mice; third, LPS-induced IUFD, IUGR and skeletal development retardation in mice is mediated, at least in part, by reactive oxygen species; fourth, LPS-induced IURD, IUGR and skeletal development retardation in mice is independent of NO production; and fifth, NAC had a dual effect on LPS-induced IUFD, IUGR and skeletal development retardation, pretreatment with NAC improves fetal survival and reverses LPS-induced IUGR and skeletal development retardation, whereas post-treatment with NAC aggravates LPS induced preterm labor; Pretreatment with AA protected against LPS-induced IUFD and reversed LPS-induced IUGR and skeletal development retardation, whereas post-treatment and pre- + post-treatment had less effect on LPS-induced IUFD; and MT protects against LPS-induced IURD, IUGR and skeletal development retardation in mice.
引文
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