锌对高同型半胱氨酸诱导鼠胚心脏畸形的干预研究
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摘要
目的
先天性心脏病是人类所有出生缺陷中最常见的疾病之一。它由多种复杂因素共同作用而来,孕期各种营养物质的缺乏及致畸剂的接触在心脏发育异常作用病因中占60%左右。高同型半胱氨酸血症能引起心脏发育异常,其自身所致的氧化应激损伤可能是重要发病环节。锌元素是体内微量元素的一种,对胚胎发育有至关重要的作用,根据其在抗氧化作用方面,推测与同型半胱氨酸诱导胚胎心脏畸形作用之间具有相关性,本实验以大鼠为实验对象,同型半胱氨酸对孕鼠致畸,建立胎鼠先天性心脏病模型。孕周给予常规剂量锌剂补充,通过胎心畸形率比较,以探讨锌元素是否能干预同型半胱氨酸对心脏发育的毒性作用,同时探讨其作用的可能机制,为孕期增补锌元素以预防先天性心脏病提供实验理论依据。
方法
本实验选用SD成年健康清洁级雌,雄大鼠各40只,常规方法交配获取孕鼠后,按体重接近随机分为5个组,每组8只:空白对照组(等量蒸留水+等量生理盐水注射)、单纯同型半胱氨酸(HCY)致畸组(等量蒸留水+8μmol/L HCY注射)、锌+HCY组(30mg/kg·d锌+8μmol/L HCY注射)、叶酸+HCY组(30mg/kg·d叶酸+8μmol/L HCY注射)、联合组(30mg/kg·d锌+30mg/kg·d叶酸+8μmol/L HCY注射)五组,分别于妊娠13,15,17,19天取材,通过切片进行胎鼠心脏组织学畸形观察;化学比色法测定各组孕鼠血清超氧化物歧化酶活力值;逆转录一聚合酶链方法检测孕鼠外周血淋巴细胞MT-I亚型基因mRNA及胚胎心脏组织的GATA-4因子mRNA表达。
结果
1.各组孕鼠各妊娠天数取材时均发现胚胎有不同程度吸收,畸形及死胎,妊娠相应天数注射HCY后,胚胎总畸形率与空白对照组相比增高(P<0.001);干预组与单纯注射HCY组比较,畸形率均明显减少(P<0.001)。
2.各妊娠天数(13,15,17,19天),HCY组胎心畸形率与对照组比较明显增加(P<0.001);干预组与HCY组比较,畸形率均明显减少(P<0.05),畸形表现为
发育延迟,心房缺如,室间隔缺损,心室缺损等。各妊娠天数胎心畸形变化呈下降趋势,期间比较差异无显著性(P>0.05)。
3. HCY组孕鼠血清CuZn-SOD活力值较对照组比较明显下降(P<0.005);干预组与HCY组比较,CuZn-SOD活力值增加,锌+HCY组及联合组(P<0.01),叶酸+HCY组(P<0.05);锌+HCY组及联合组与叶酸+HCY组比较(P<0.05)。
4. HCY组孕鼠外周血淋巴细胞MT-I亚型基因mRNA表达较对照组明显下降:HCY组与叶酸+HCY组(P<0.001),锌+HCY与联合组(P<0.05);干预组与HCY组比较表达均明显增加,叶酸+HCY组(P<0.01),锌+HCY及联合组(P<0.001);干预组间比较:叶酸+HCY组与另两组比较(P<0.001)。
5.各组孕鼠各妊娠天数胎鼠心脏GATA-4因子mRNA表达比较:各组间未见明显改变,差别无统计学意义(P>0.05);胎鼠心脏GATA-4因子妊娠期间表达呈逐渐增高趋势,但各妊娠天数间比较差异无显著性(P>0.05)。
结论
1.造模成功,HCY对鼠胚胎心脏发育具有毒性作用,表现为发育延迟,心房缺如,室间隔缺损,心室缺损及大体畸形等,且畸形在早孕期更易发生。
2.孕期补锌胎心畸形率较HCY组显著下降,表明补锌能有效地干预HCY对鼠胚胎心脏发育的毒性作用,且干预在孕早期更为显著,提示孕早期补锌对胎心发育具有保护作用。
3.孕期锌与叶酸两者同时补充,胎心畸形率较HCY组显著下降,提示可能存在协同作用。
4.补锌组孕鼠血清Cu-ZnSOD活力值较HCY组显著增高,提示锌元素有可能是通过抑制氧化反应的发生进而发挥干预作用的。
5.补锌组孕鼠外周血淋巴细胞MT-I型基因表达较HCY组显著增高,而胎鼠心脏GATA-4因子mRNA表达无明显改变,提示孕期补锌可能通过某种特定的机制诱导MT蛋白的产生,通过后者的强抗氧化机制干预HCY对胚胎心脏作用产生的畸形作用。
Objective
Congenital heart disease(CHD) is one of the most common diseases of all human birth defects.Genenal speaking,it is believed that CHD is the role of a variety of complex factors come together, The lack of the various nutrition and teratogenic agent contacts during pregnancy in the cause of heart abnormality to account for about 60%. The research reported that blood hyperhomocysteinemia can cause abnormal heart development, which own injury caused by oxidative stress may be an important link in the pathogenesis. Zinc is one type of a variety of trace elements, which plays a vital role in the embryonic development and its antioxidant role, which speculation has the same type of correlation between homocysteine, Our experiment made the rats for experimental objects, Homocysteine teratogenic on pregnant rats, and establish of fetal mouse model of congenital heart disease. Gestational age for routine dose of zinc and folic acid supplement, through observe and compare abnormal fetal heart rate of each group ,To explore Whether Zinc can inhibit homocysteine in the development of cardiac toxicity, and explore the possible mechanism of its role,For added Zinc during pregnancy prevention of congenital heart disease to provide experimental theory.
Methods
Experimental use of this Clean-SD adult male and female rats 40, through conventional method of mating access to pregnant rats, according to the weight close to randomly divided into five groups: the control group (steamed in water + NS injection), simply homocysteine (HCY) teratogenic (steamed in water + HCY injection), Zn + HCY group (30 mg / kg ? d zinc+ HCY injection), Folic acid + HCY group (30 mg / kg ? d folic acid + HCY injection), TheJoint group (30 mg / kg ? d zinc +30 mg / kg ? d folic acid+ HCY injection) five groups, based on pregnancy 13,15,17,19 days, through histological sections observed the fetal cardiac malformations, through chemical colorimetric method detect the pregnant rats serum superoxide dismutase (SOD) activity value; through the method of reverse transcription- polymerase chain reaction (RT-PCR) to test pregnant rats serum MT mRNA and protein of the embryo heart tissue factor GATA-4 mRNA expression.
Results
1. Groups of pregnant rats during pregnancy days based embryos were found in varying degrees absorption, deformities and stillbirths, deformities of performance for the delay, atrial absence, ventricular septal defect, ventricular defect and general malformations.
2. HCY abnormal fetal heart rate and group 19 days fetal heart weight compared with the control group was significantly increased (P <0.001); intervention groups compared with HCY, the deformity rate were significantly reduced (P <0.05), number of days of pregnancy fetal heart deformities in a downward trend, but the difference was not statistically significant (P> 0.05).
3. HCY rat serum progesterone group CuZn-SOD value compared with the control group was significantly decreased (P <0.005); intervention groups compared with HCY, CuZn-SOD activity was increased, zinc + HCY group and the combination group (P <0.01), leaf Acid + HCY group (P <0.05) + zinc HCY Group and the Joint Group and folic acid + HCY group (P <0.05).
5. HCY rat serum progesterone group metallothionein (MT protein) mRNA expression compared with the control group decreased significantly, HCY group and folic acid + HCY group (P <0.001), Zn + HCY and the combined group (P <0.05); intervention group and HCY group, MT mRNA expression was significantly increased, folic acid + HCY group (P <0.01), and Zn + HCY joint group (P <0.001) between group interventions: folic acid + HCY group and the other two groups, MT protein mRNA expression (P <0.001).
6. Groups of pregnant rats pregnancy days of fetal heart factor GATA-4 mRNA expression comparison: each group there was no obvious change, the difference was not statistically significant (P> 0.05), fetal heart GATA-4 expression of a factor during pregnancy gradually increasing trend, but the comparison between the number of days of pregnancy showed no significant difference (P> 0.05).
Conclusions
1. Successfully modeling,Homocysteine can induce mouse embryonic heart toxicity, developmental deformities performance for the delay, atrial absence, ventricular septal defect, ventricular defect and largely deformed, with the exception of cardiac malformation, able to observe other aspects of abnormal situation, but don’t detect, must further experimental studies to be confirmed.
2. Zinc can effectively antagonize the mouse embryonic heart development toxicity which induced by homocysteine.
3.Pregnant at the same time added there was no conflict between the two roles, there may be synergies, need further study to confirm.
4. Zinc may be through inhibiting the oxidation reaction to the occurrence of HCY play the role of antagonist, and Zinc's role in this regard than the more folic acid significantly.
5. Pregnancy may be added Zinc through a particular mechanism induced MT protein produced by the latter's strong anti-oxidation mechanism HCY antagonistic role of the embryonic heart deformity role.
先天性心脏病是人类所有出生缺陷中最常见的疾病之一。它由多种复杂因素共同作用而来,孕期各种营养物质的缺乏及致畸剂的接触在心脏发育异常作用病因中占60%左右。高同型半胱氨酸血症能引起心脏发育异常,其自身所致的氧化应激损伤可能是重要发病环节。锌元素是体内微量元素的一种,对胚胎发育有至关重要的作用,根据其在抗氧化作用方面,推测与同型半胱氨酸诱导胚胎心脏畸形作用之间具有相关性,本实验以大鼠为实验对象,同型半胱氨酸对孕鼠致畸,建立胎鼠先天性心脏病模型。孕周给予常规剂量锌剂补充,通过胎心畸形率比较,以探讨锌元素是否能干预同型半胱氨酸对心脏发育的毒性作用,同时探讨其作用的可能机制,为孕期增补锌元素以预防先天性心脏病提供实验理论依据。
方法
本实验选用SD成年健康清洁级雌,雄大鼠各40只,常规方法交配获取孕鼠后,按体重接近随机分为5个组,每组8只:空白对照组(等量蒸留水+等量生理盐水注射)、单纯同型半胱氨酸(HCY)致畸组(等量蒸留水+8μmol/L HCY注射)、锌+HCY组(30mg/kg·d锌+8μmol/L HCY注射)、叶酸+HCY组(30mg/kg·d叶酸+8μmol/L HCY注射)、联合组(30mg/kg·d锌+30mg/kg·d叶酸+8μmol/L HCY注射)五组,分别于妊娠13,15,17,19天取材,通过切片进行胎鼠心脏组织学畸形观察;化学比色法测定各组孕鼠血清超氧化物歧化酶活力值;逆转录一聚合酶链方法检测孕鼠外周血淋巴细胞MT-I亚型基因mRNA及胚胎心脏组织的GATA-4因子mRNA表达。
结果
1.各组孕鼠各妊娠天数取材时均发现胚胎有不同程度吸收,畸形及死胎,妊娠相应天数注射HCY后,胚胎总畸形率与空白对照组相比增高(P<0.001);干预组与单纯注射HCY组比较,畸形率均明显减少(P<0.001)。
2.各妊娠天数(13,15,17,19天),HCY组胎心畸形率与对照组比较明显增加(P<0.001);干预组与HCY组比较,畸形率均明显减少(P<0.05),畸形表现为
发育延迟,心房缺如,室间隔缺损,心室缺损等。各妊娠天数胎心畸形变化呈下降趋势,期间比较差异无显著性(P>0.05)。
3. HCY组孕鼠血清CuZn-SOD活力值较对照组比较明显下降(P<0.005);干预组与HCY组比较,CuZn-SOD活力值增加,锌+HCY组及联合组(P<0.01),叶酸+HCY组(P<0.05);锌+HCY组及联合组与叶酸+HCY组比较(P<0.05)。
4. HCY组孕鼠外周血淋巴细胞MT-I亚型基因mRNA表达较对照组明显下降:HCY组与叶酸+HCY组(P<0.001),锌+HCY与联合组(P<0.05);干预组与HCY组比较表达均明显增加,叶酸+HCY组(P<0.01),锌+HCY及联合组(P<0.001);干预组间比较:叶酸+HCY组与另两组比较(P<0.001)。
5.各组孕鼠各妊娠天数胎鼠心脏GATA-4因子mRNA表达比较:各组间未见明显改变,差别无统计学意义(P>0.05);胎鼠心脏GATA-4因子妊娠期间表达呈逐渐增高趋势,但各妊娠天数间比较差异无显著性(P>0.05)。
结论
1.造模成功,HCY对鼠胚胎心脏发育具有毒性作用,表现为发育延迟,心房缺如,室间隔缺损,心室缺损及大体畸形等,且畸形在早孕期更易发生。
2.孕期补锌胎心畸形率较HCY组显著下降,表明补锌能有效地干预HCY对鼠胚胎心脏发育的毒性作用,且干预在孕早期更为显著,提示孕早期补锌对胎心发育具有保护作用。
3.孕期锌与叶酸两者同时补充,胎心畸形率较HCY组显著下降,提示可能存在协同作用。
4.补锌组孕鼠血清Cu-ZnSOD活力值较HCY组显著增高,提示锌元素有可能是通过抑制氧化反应的发生进而发挥干预作用的。
5.补锌组孕鼠外周血淋巴细胞MT-I型基因表达较HCY组显著增高,而胎鼠心脏GATA-4因子mRNA表达无明显改变,提示孕期补锌可能通过某种特定的机制诱导MT蛋白的产生,通过后者的强抗氧化机制干预HCY对胚胎心脏作用产生的畸形作用。
Objective
Congenital heart disease(CHD) is one of the most common diseases of all human birth defects.Genenal speaking,it is believed that CHD is the role of a variety of complex factors come together, The lack of the various nutrition and teratogenic agent contacts during pregnancy in the cause of heart abnormality to account for about 60%. The research reported that blood hyperhomocysteinemia can cause abnormal heart development, which own injury caused by oxidative stress may be an important link in the pathogenesis. Zinc is one type of a variety of trace elements, which plays a vital role in the embryonic development and its antioxidant role, which speculation has the same type of correlation between homocysteine, Our experiment made the rats for experimental objects, Homocysteine teratogenic on pregnant rats, and establish of fetal mouse model of congenital heart disease. Gestational age for routine dose of zinc and folic acid supplement, through observe and compare abnormal fetal heart rate of each group ,To explore Whether Zinc can inhibit homocysteine in the development of cardiac toxicity, and explore the possible mechanism of its role,For added Zinc during pregnancy prevention of congenital heart disease to provide experimental theory.
Methods
Experimental use of this Clean-SD adult male and female rats 40, through conventional method of mating access to pregnant rats, according to the weight close to randomly divided into five groups: the control group (steamed in water + NS injection), simply homocysteine (HCY) teratogenic (steamed in water + HCY injection), Zn + HCY group (30 mg / kg ? d zinc+ HCY injection), Folic acid + HCY group (30 mg / kg ? d folic acid + HCY injection), TheJoint group (30 mg / kg ? d zinc +30 mg / kg ? d folic acid+ HCY injection) five groups, based on pregnancy 13,15,17,19 days, through histological sections observed the fetal cardiac malformations, through chemical colorimetric method detect the pregnant rats serum superoxide dismutase (SOD) activity value; through the method of reverse transcription- polymerase chain reaction (RT-PCR) to test pregnant rats serum MT mRNA and protein of the embryo heart tissue factor GATA-4 mRNA expression.
Results
1. Groups of pregnant rats during pregnancy days based embryos were found in varying degrees absorption, deformities and stillbirths, deformities of performance for the delay, atrial absence, ventricular septal defect, ventricular defect and general malformations.
2. HCY abnormal fetal heart rate and group 19 days fetal heart weight compared with the control group was significantly increased (P <0.001); intervention groups compared with HCY, the deformity rate were significantly reduced (P <0.05), number of days of pregnancy fetal heart deformities in a downward trend, but the difference was not statistically significant (P> 0.05).
3. HCY rat serum progesterone group CuZn-SOD value compared with the control group was significantly decreased (P <0.005); intervention groups compared with HCY, CuZn-SOD activity was increased, zinc + HCY group and the combination group (P <0.01), leaf Acid + HCY group (P <0.05) + zinc HCY Group and the Joint Group and folic acid + HCY group (P <0.05).
5. HCY rat serum progesterone group metallothionein (MT protein) mRNA expression compared with the control group decreased significantly, HCY group and folic acid + HCY group (P <0.001), Zn + HCY and the combined group (P <0.05); intervention group and HCY group, MT mRNA expression was significantly increased, folic acid + HCY group (P <0.01), and Zn + HCY joint group (P <0.001) between group interventions: folic acid + HCY group and the other two groups, MT protein mRNA expression (P <0.001).
6. Groups of pregnant rats pregnancy days of fetal heart factor GATA-4 mRNA expression comparison: each group there was no obvious change, the difference was not statistically significant (P> 0.05), fetal heart GATA-4 expression of a factor during pregnancy gradually increasing trend, but the comparison between the number of days of pregnancy showed no significant difference (P> 0.05).
Conclusions
1. Successfully modeling,Homocysteine can induce mouse embryonic heart toxicity, developmental deformities performance for the delay, atrial absence, ventricular septal defect, ventricular defect and largely deformed, with the exception of cardiac malformation, able to observe other aspects of abnormal situation, but don’t detect, must further experimental studies to be confirmed.
2. Zinc can effectively antagonize the mouse embryonic heart development toxicity which induced by homocysteine.
3.Pregnant at the same time added there was no conflict between the two roles, there may be synergies, need further study to confirm.
4. Zinc may be through inhibiting the oxidation reaction to the occurrence of HCY play the role of antagonist, and Zinc's role in this regard than the more folic acid significantly.
5. Pregnancy may be added Zinc through a particular mechanism induced MT protein produced by the latter's strong anti-oxidation mechanism HCY antagonistic role of the embryonic heart deformity role.
引文
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17 张亨山。金属硫蛋白的抗过氧化作用。 [J]:国外医学.卫生学分册,1994年02期 68-70。
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[4] Charlotte A. Hobbs, Sadia Malik, Weizhi Zhao,etal. Maternal Homocysteine and Congenital Heart Defects. J. Am. Coll. Cardiol. 2006,47:683-685.
[5]Miguel A M, José L U, María I A S. Amores-sánchez roles of homocysteine in cell metabolism old and new functions[J].Eur J Biochem,2001,268:3871-3882.
[6]Infante R, Rivard G E, Yotov W V. Perinatal reference intervals for plasma homocysteine and factors influencing its concentration [J].Clin Chem,2002,48(7):1100-1102.
[7]Marit J B, Regine P M S T, Robert E P. Cardiac outflow tract malformations in chick embryos exposed to homocysteine [J].Cardiovascular Research,2004,64:365-373.
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[9] Hobbs CA,Cleves MA,Zhao W,etal. Congenital heart defects and maternal biomarkers of oxidative stress.Am J Clin Nutr. 2005 Sep,82(3):598-604.
[10] S. Jill James,Stepan Melnyk, Marta Pogribna,etal. Elevation in S-Adenosylhomo -cysteine and DNA Hypomethylation: Potential Epigenetic Mechanism forHomocysteine-Related Pathology. J. Nutr., Aug 2002,32: 2361.
[11]Mario M, Laura E C, Nelly Z, et al. Randomized controlled trial of prenatal zinc supplementation and fetal bone growth[J]. Am J Clin Nutr,2004,79:826-830.
[12] Shah D, Sachdev HP. Zinc deficiency in pregnancy and fetal outcome. Nutr Rev. 2006 Jan,64(1):15-30.
[13]Carl L K, Lynn A H, Louise L, et al. Developmental consequences of trace mineral deficiencies in rodents: Acute and long-term effects[J].The Journal of Nutritional,2003,133:1477.
[14] J.Y. Duffy,G.J. Overmann, C.L. Keen,etal. Cardiac abnormalities induced by zinc deficiency are associated with alterations in the expression of genes regulated by the zinc-finger transcription factor GATA-4.[J].Birth Defects,2004,71(2):102-109.
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