孕期野百合碱暴露对胎鼠胆固醇水平的影响
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摘要
目的研究孕期野百合碱(monocrotaline,MCT)暴露的胎鼠胆固醇水平改变及其原因。方法受孕Wistar大鼠于孕9～20天(gestation day,GD)每天灌胃给予20 mg·kg-1MCT,孕鼠于GD 20处死,取雌雄性胎鼠并收集母胎血、胎盘和胎肝,检测母血胆汁酸及母、胎血胆固醇水平,以及胎盘胆固醇转运和胎肝胆固醇合成、转运相关基因表达。结果与对照组相比,MCT组母血胆汁酸水平增高,总胆固醇(total cholesterol,TCH)水平升高。雄性胎血TCH和低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)水平升高,雌雄性胎盘低密度脂蛋白受体(low-density lipoprotein receptor,LDLR)、B类I型清道夫受体(scavenger receptor class B type I,SR-B1)、三磷酸腺苷结合盒转运体A1(adenosine triphosphate binding cassette transporter A1,ABCA1)基因表达上调,而雌雄性胎肝3-羟基-3-甲基戊二酰辅酶A还原酶(3-hydroxy-3-methylglutaryl coenzyme A reductase,HMGCR)、SR-B1、LDLR mR NA表达下调。结论孕期MCT暴露所致母鼠血胆汁酸水平增高可引起母鼠高胆固醇血症,增加胎盘胆固醇转运体表达,导致胎鼠高胆固醇血症。胎肝胆固醇转运相关基因表达降低,提示孕期MCT暴露可造成胎肝的胆固醇代谢稳态改变。
Objective To explore the changes and causes of cholesterol level in fetal rats from cholestasis mother induced by monocrotaline(MCT) exposure. Methods Pregnant Wistar rats were treated with MCT(20 mg·kg-1·d-1) from gestation days(GDs) 11 to 20, and rats were sacrificed at GD 20. Maternal and fetal blood, placenta and fetal liver were collected. Cholesterol levels in maternal and fetal bloods were determined, and expression of placental cholesterol transporter and fetal liver cholesterol-related genes were examined. Results Compared with the control group,maternal blood bile acid and total cholesterol(TCH) levels were enhanced by MCT treatment. Male fetal blood TCH and low-density lipoprotein cholesterol(LDL-C) levels increased. Expression of low-density lipoprotein receptor(LDLR), scavenger receptor class B type I(SR-B1) and triphosphate binding cassette transporter A1(ABCA1) were up-regulated in male and female fetal placentae from MCT group. In addition, expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase(HMGCR), SR-B1, and LDLR were down-regulated in male and female fetal liver. Conclusion Maternal cholestasis induced by MCT exposure caused hypercholesterolemia in maternal and in-creased the expression of placental cholesterol transporter, leading to a high cholesterol level in fetal rats. Changes in the expression of cholesterol transporter in fetal liver suggest that MCT exposure during pregnancy may result in alteration of cholesterol homeostasis in fetal liver.
Objective To explore the changes and causes of cholesterol level in fetal rats from cholestasis mother induced by monocrotaline(MCT) exposure. Methods Pregnant Wistar rats were treated with MCT(20 mg·kg-1·d-1) from gestation days(GDs) 11 to 20, and rats were sacrificed at GD 20. Maternal and fetal blood, placenta and fetal liver were collected. Cholesterol levels in maternal and fetal bloods were determined, and expression of placental cholesterol transporter and fetal liver cholesterol-related genes were examined. Results Compared with the control group,maternal blood bile acid and total cholesterol(TCH) levels were enhanced by MCT treatment. Male fetal blood TCH and low-density lipoprotein cholesterol(LDL-C) levels increased. Expression of low-density lipoprotein receptor(LDLR), scavenger receptor class B type I(SR-B1) and triphosphate binding cassette transporter A1(ABCA1) were up-regulated in male and female fetal placentae from MCT group. In addition, expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase(HMGCR), SR-B1, and LDLR were down-regulated in male and female fetal liver. Conclusion Maternal cholestasis induced by MCT exposure caused hypercholesterolemia in maternal and in-creased the expression of placental cholesterol transporter, leading to a high cholesterol level in fetal rats. Changes in the expression of cholesterol transporter in fetal liver suggest that MCT exposure during pregnancy may result in alteration of cholesterol homeostasis in fetal liver.
引文
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[16]Dan X,Luo H W,Wen H,et al.Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine-exposed female adult rat offspring[J].The FASEB Journal,2018,32(10):5563-5576.
[2]Papacleovoulou G,Abu-Hayyeh S,Nikolopoulou E,et al.Maternal cholestasis during pregnancy programs metabolic disease in offspring[J].J Clin Invest,2013,123(7):3172-3181.
[3]Robertson J,Stevens K.Pyrrolizidine alkaloids:occurrence,biology,and chemical synthesis[J].Natural Product Reports,2016,34(1):62-89.
[4]Ma C,Liu Y,Zhu L,et al.Determination and regulation of hep atotoxic pyrrolizidine alkaloids in food:A critical review of recent research[J].Food and Chemical Toxicology,2018,119:50-60.
[5]Rolf T,Dominique L,Dieter M,et al.Traditional Chinese Medicine(TCM)and Herbal Hepatotoxicity:RUCAM and the Role of Novel Diagnostic Biomarkers Such as MicroRNAs[J].Medicines,2016,3(3):18.
[6]Yao J,Li C G,Gong L K,et al.Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice[J].Acta Pharmacologica Sinica,2014,35(2):292-300.
[7]Li X,Yang X,Xiang E,et al.Maternal-Fetal Disposition and Metabolism of Retrorsine in Pregnant Rats[J].Drug Metabolism and Disposition,2018,46(4):422-428.
[8]Guo Y,Ma Z,Kou H,et al.Synergistic effects of pyrrolizidine alkaloids and lipopolysaccharide on preterm delivery and intrauterine fetal death in mice[J].Toxicology Letters,2013,221(3):212-218.
[9]Forsch K,Sch ning V,Disch L,et al.Development of an,in vitro,screening method of acute cytotoxicity of the pyrrolizidine alkaloid lasiocarpine in human and rodent hepatic cell lines by increasing susceptibility[J].Journal of Ethnopharmacology,2018,217:134-139.
[10]Hill E M,Robinson L A,Abdul-Sada A,et al.Arbuscular Mycorrhizal Fungi and Plant Chemical Defence:Effects of Colonisation on Aboveground and Belowground Metabolomes[J].Journal of Chemical Ecology,2018,44(2):198-208.
[11]Xiong A,Yang F,Fang L,et al.Metabolomic and Genomic Evidence for Compromised Bile Acid Homeostasis by Senecionine,a Hepatotoxic Pyrrolizidine Alkaloid[J].Chemical Research in Toxicology,2014,27(5):775-786.
[12]Trapani L,Segatto M,Pallottini V.Regulation and deregulation of cholesterol homeostasis:The liver as a metabolic"power station"[J].World Journal of Hepatology,2012,4(6):184-190.
[13]Woollett L A.Review:Transport of maternal cholesterol to the fetal circulation[J].Placenta,2011,32(supp-S2):S218-S221.
[14]Woollett L A.Maternal cholesterol in fetal development:transport of cholesterol from the maternal to the fetal circulation[J].American Journal of Clinical Nutrition,2005,82(6):1155-1161.
[15]Jin Z,Chunyan Z,Hanwen L,et al.Two intrauterine programming mechanisms of adult hypercholesterolemia induced by prenatal nicotine exposure in male offspring rats[J].The FASEBJournal,2018,33(1):1110-1123.
[16]Dan X,Luo H W,Wen H,et al.Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine-exposed female adult rat offspring[J].The FASEB Journal,2018,32(10):5563-5576.