母亲孕期高脂暴露对子代代谢健康的影响及其机制研究
发布时间：2019-05-16 22:18
【摘要】：第一部分母亲孕期高甘油三酯血症通过重编程子代瘦素水平诱发成年期高血压 目的：证实母亲孕晚期高甘油三酯(TG)血症可增加出生子代成年高血压的发生风险,探讨瘦素(leptin)基因的甲基化改变在其中发挥的作用。材料和方法：临床随访不同出生体重的个体在学龄前期、学龄期和成年期的身高、体重和血压的变化并留取部分人群血清检测leptin水平。同时临床调查2687例孕妇孕晚期的血脂数据和子代出生的基本信息,并留取母亲血和脐带血检测血脂、脂肪酸以及leptin等的水平；高脂喂养建立孕期高脂血症大鼠模型,留取母亲孕期血清检测血脂水平,证实孕晚期存在高甘油三酯血症。收集子代大鼠各个年龄段(胎鼠,3周,8周,6月,1年)的淋巴细胞和／或脂肪组织以及肾脏,分别检测leptin基因的表达和肾小动脉管壁厚度。用亚硫酸盐测序方法检测人脐血和外周血淋巴细胞leptin基因的表达和甲基化水平。同样方法检测胎鼠和3周大鼠的脂肪leptin基因的甲基化以及3周大鼠淋巴细胞的甲基化变化。利用胎鼠期间分离出来的骨髓来源的间充质干细胞(MSCs)进行深入的机制探讨。MSc在成脂分化过程中加不同浓度的脂肪酸,检测高浓度的脂肪酸对成脂分化过程中leptin基因表达和甲基化的作用。 结果：出生巨大儿的个体从儿童期一直到成年时期均表现出持续升高的血清leptin水平,且在成年期血压明显高于正常出生体重的成年个体,且30-50岁的高血压发生率在巨大儿组明显升高,尽管两组之间的体重指数(BMI)无显著差异。巨大儿和正常出生体重两组的母亲孕期血脂比较结果提示巨大儿组母血甘油三酯水平(mTG)显著高于对照组。因此,我们再根据临床调查的2687例孕晚期母亲血TG值计算平均值为3.28mM,然后按照3.28mM把数据分为高母亲血脂组(mTG3.28mM)和低母亲血脂组(mTG3.28mM),结果发现高mTG组母亲出生的子代脐带血和学龄前期的外周血血清leptin水平均显著升高,而且无论是出生时还是学龄前阶段,血清leptin水平与母亲血清TG水平呈显著正相关。高脂喂养动物出生子代自8周起体重已趋于同龄对照组大鼠,但是血压显著高于对照组,1年时出现明显高血压,伴有肾小动脉管壁的明显增厚。高脂母亲出生的子代大鼠各个年龄段的血清leptin水平表现为持续升高,同时各个年龄段的脂肪组织和淋巴细胞leptin基因均持续显著的高表达。高TG母亲出生的新生儿和学龄前儿童的淋巴细胞leptin基因表达显著高于对照组,同时伴随着甲基化水平的显著降低。与临床结果一致,高脂喂养母亲子代的胎鼠脂肪、3周龄的皮下脂肪和内脏脂肪均出现leptin基因的高表达伴随着低甲基化状态,同时3周龄子代大鼠的淋巴细胞leptin也呈现高表达和低甲基化。体外MSC诱导分化过程中加高浓度的脂肪酸可增加leptin基因的表达和促进去甲基化酶TET1的高表达,导致leptin基因的低甲基化。 结论：母亲孕期高脂暴露可通过修饰leptin基因的甲基化影响其表达从而诱导子代成年高血压的发生。 第二部分：母亲孕期高甘油三酯血症可通过调节leptin介导的胆固醇代谢通路增加子代高胆固醇血症的风险 目的：探讨母亲孕期高甘油三酯血症导致的持续升高的leptin水平是否通过调节胆固醇分解代谢的关键酶胆固醇7a-羟化酶(CYP7α1)的表达,从而增加子代发生高胆固醇血症的风险。 材料与方法：随机电话随访2006-2007年在我院分娩出生的儿童250例,收集自愿回随访门诊体检的49例学龄前期儿童(3-6岁)的血清检测血清leptin、血脂四项等水平,同时回顾性调查其母亲孕期的血脂水平和出生相关资料。利用孕期高脂喂养大鼠模型进一步验证高脂子代3周龄大小时血清leptin以及血脂水平,同时用化学发光法检测3周龄子代大鼠肝脏组织匀浆上清血脂水平。Real-time PCR和Western分别用于检测3周子代大鼠肝脏组织胆固醇代谢关键酶的表达。利用体外培养肝细胞系HepG2进行机制的研究,观察leptin是否可浓度依赖性的调节通路因子LEPR-JAK2-STAT3的表达,同时调控CYP7α1的表达；siRNA靶向干扰转录因子后进一步证实leptin刺激后通过STAT3发挥调节作用；免疫共沉淀(CHIP)试验证实转录因子STAT3可结合到CYP7α1基因启动子区域发挥调控作用。 结果：高mTG组出生子代儿童血清leptin、胆固醇水平显著高于mTG组,儿童血清leptin水平与胆固醇水平呈显著正相关。高脂喂养大鼠出生的子代3周龄时血清leptin和胆固醇水平也呈现显著升高,肝脏组织匀浆上清总胆固醇水平在高脂子代组显著高于正常喂养子代组,同时伴有胆固醇降解关键酶CYP7α1的显著下调。体外细胞实验结果显示：随着leptin浓度的不断增加,通路因子LEPR、 JAK2、STAT3表达浓度依赖性上调,而高浓度的leptin可下调CYP7α1的表达。靶向干扰STAT3后,leptin刺激下CYP7α1表达不再浓度下调,CHIP试验结果进一步提示转录因子STAT3可结合CYP7α1基因启动子区域发挥调控作用。 结论：母亲孕期高甘油三酯血症出生子代儿童期高胆固醇血症风险增加,孕期高脂诱导的子代持续高leptin水平可通过LEPR-JAK2-STAT3通路调控胆固醇降解的关键酶CYP7α1基因的表达。 第三部分：孕期高脂暴露诱发的子代脂质代谢异常的传代机制研究 目的：探讨亲代母亲孕期高脂饮食是否对子一代(F1)脂质代谢产生影响以及这种不良影响是否能通过配子传至子二代(F2) 材料与方法：建立孕期高脂喂养(HFD)的大鼠模型,观察出生的F1代在恢复正常喂养后各年龄段的体重和脂质代谢,再用F1代分别与正常异性大鼠交配以及高脂子代组内交配,观察HFD-F1♂以及HFD-F1♀出生的F2代的各年龄段体重以及脂质代谢变化。Real-time PCR方法筛查F1代、F2代肝脏和F1精子中脂代谢相关的印记基因,筛选出母源印记基因Igf2和父源印记基因Igf2r做进一步的机制研究。再用亚硫酸盐修饰测序方法分别检测F2成年肝脏中这两个印记基因的甲基化改变,来探讨亲代异常宫内环境暴露影响子代的脂质代谢的传代机制。结果：高脂喂养出生的F1代3周内体重显著高于正常对照组,但是8周起两组之间无显著差异。HFD-F1在3周时出现明显的血脂异常,表现为TG, TC, HDL和LDL水平显著高于对照F1,8周和12周两组间无明显差异,但是HFD-F1在6月和1年时出现明显的TG的升高,1年的时候同时出现LDL的升高和HDL的下降。尽管F1代恢复正常饮食,且受孕前和孕期均无高脂血症,但是HFD-F1(?)出生的F2代在8周、12周及6月分别表现为血TG水平的显著升高,且在12周和6月还伴随着LDL的升高；与此不同的是,HFD-F1(?)出生的F2与对照组间差异不明显。我们分别筛查了F1和F2肝脏中脂代谢相关的基因基因,发现母源印记基因Igf2和父源印记基因Igf2r的甲基化持续的高表达,同时在F1精子和F2胎肝上验证这两个基因均呈现高表达。因此我们检测了F2肝脏中的印记基因Igf2和Igf2r的甲基化改变,结果提示HFD-F1(?)出生的F2成年肝脏的Igf2出现2个位点的低甲基化,Igf2r基因的总甲基化显著下降,伴有5个位点的低甲基化。 结论：亲代孕期高脂饮食可致子一代脂质代谢异常,异常的脂代谢变化可通过子一代的精子传至子二代,导致子二代成年期血脂代谢异常。
[Abstract]:The first part of mother's hypertriglyceridemia induced a one-year high blood pressure by reprogramming the level of leptin in the offspring Objective: To confirm that the high triglyceride (TG) in the mother trimester of pregnancy can increase the incidence of adult high blood pressure in the offspring. To explore the role of leptin in the methylation of leptin gene Materials and Methods: The change of height, body weight and blood pressure of the individual with different birth weight in the pre-school period, the normal period and the adulthood, and the serum detection of leptin in some of the population Ping. At the same time,2687 pregnant women were surveyed with the basic information of blood lipid data and the birth of the offspring, and the levels of blood fat, fatty acid and leptin were detected by mother blood and umbilical cord blood. The model of hyperlipidemic rats during pregnancy was established by high-fat feeding. It is confirmed that high triglyceride blood is present in the late stage of the pregnancy The expression of the leptin gene and the wall thickness of the renal arterioles were detected by collecting the lymphocytes and/ or the adipose tissue and the kidney of each age group (fetal rat,3-week,8-week,6-month,1 year) of the offspring rats. degree. Detection of the expression and methylation of leptin in human umbilical cord blood and peripheral blood lymphocytes by a sulfite sequencing method Ping. The methylation of the leptin gene in the fetal and 3-week rats and the methylation of the 3-week rat lymphocytes were also detected by the same method. In-depth mechanism of bone marrow-derived mesenchymal stem cells (MSCs) isolated from the fetal rat The effect of high concentration of fatty acid on the expression and methylation of leptin in the process of adipocyte differentiation was studied by adding different concentrations of fatty acid to the process of adipocyte differentiation. Results: The level of serum leptin, which was continuously elevated from childhood to adulthood, was observed in the individual from childhood to adulthood, and the blood pressure in adulthood was significantly higher than that of the normal birth weight, and the incidence of hypertension in the 30-50 year of age was in the large group. The significant increase, although the body mass index (BMI) between the two groups was not significant The results showed that the serum triglyceride level (mTG) was significantly higher in the mothers with large and normal birth weight. In the control group, therefore, we calculated the mean value of the maternal blood TG value of 3.28 mM and then divided the data into the high-mother blood-lipid group (mTG3.28 mM) and the low-mother blood-lipid group (mTG3.28) according to the 2687 cases of the clinical investigation. The results showed that the level of serum leptin in the peripheral blood of the mothers of the high mTG group was increased significantly, and the level of leptin and the level of TG in the mother serum were significantly higher either at the time of birth or in the pre-school stage. The weight of the birth of the high-fat-fed animal was increased from 8 weeks to the control group in the same age, but the blood pressure was significantly higher than that in the control group. The level of leptin in each age group of the offspring of the high-fat mother was increased continuously, while the leptin gene of the adipose tissue and the lymphocytes of all age groups continued to be significant. High expression. The expression of lepitin gene in the neonatal and pre-school children born by the high TG mother was significantly higher than that of the control group, accompanied by a significant increase in the level of methylation. In the same time, the high expression of leptin was associated with the low methylation status of the fetal rat fat,3-week-old subcutaneous fat and visceral fat of the high-fat-fed mother, and the high expression and the low level of the lymphocyte letin in the 3-week-old offspring were also presented. The high concentration of fatty acid in the induction and differentiation of MSC in vitro can increase the expression of leptin gene and promote the high expression of the demethylase TET1, leading to the low leptin gene. Conclusion: The high-fat exposure of mother can influence its expression by modifying the methylation of leptin gene, so as to induce the adult height of the offspring. The second part: hypertriglyceridemia in the mother's pregnancy can increase the offspring's height by adjusting the leptin-mediated cholesterol metabolism pathway cholesterol Objective of the study of the risk of hypertriglyceridemia: to explore whether the level of leptin, which is caused by hypertriglyceridemia during pregnancy, is increased by regulating the expression of the key enzyme-cholesterol 7a-hydroxylase (CYP7-1) in cholesterol catabolism, thus increasing the generation of offspring. The risk of hypercholesteremia. Materials and Methods:250 cases of children born in our hospital from 2006 to 2007 were followed up by random telephone, and the serum of 49 pre-school children (3-6 years) who received a voluntary follow-up visit were collected. The levels of tin, blood lipid, and the like, and the mother's pregnancy were retrospectively investigated. The serum leptin and blood lipid level of 3-week-old offspring of high-fat children were further verified by high-fat-fed rat model during pregnancy, and the liver of 3-week-old offspring was detected by the chemiluminescence method. The blood lipid level of the homogenate of the dirty tissue was detected by Real-time PCR and Western blot. The expression of the key enzyme of cholesterol metabolism was studied. The expression of LEPR-JAK2-STAT3 was regulated by the mechanism of the in vitro culture of the liver cell line HepG2, and the expression of CYP7-1 was also regulated. STAT3 plays a regulating role; the immune co-precipitation (CHIP) test confirms that the transcription factor STAT3 can bind to the CYP7-1 gene The results showed that the serum leptin and cholesterol in the children with high mTG were significantly higher than those in the mTG group, and the serum leptin in the children was higher than that of the mTG group. There was a significant positive correlation between the level of cholesterol and the level of cholesterol. The level of serum leptin and cholesterol in high-fat-fed rats increased significantly, and the total cholesterol level in the liver tissue homogenate was significantly higher in the high-fat offspring than in the normal-feeding progeny group, accompanied by a cholesterol-degrading effect. The results of in vitro cell experiment show that the expression of LEPR, JAK2 and STAT3 in the pathway is up-regulated with the increase of leptin concentration, while the high concentration of lepti N The expression of CYP7-1 was downregulated. After the target of STAT3, the expression of CYP7-1 under the stimulation of leptin was no longer reduced, and the results of CHIP test further suggested that transcription factor STAT3 could bind to CYP7-1. Conclusion: The risk of high-cholesteremia in the children with hypertriglyceridemia during pregnancy is increased, and the high-fat-induced high-fat content of the offspring during pregnancy can be regulated by the LEPR-JAK2-STAT3 pathway. Expression of the key enzyme CYP7-1 gene in the third part: high-fat exposure during pregnancy induced Objective: To investigate the effect of high-fat diet on the lipid metabolism of the subgeneration (F1) in the parent mother during pregnancy, and to study the effect of the high-fat diet on the lipid metabolism of the offspring (F1). whether the adverse effect can be passed through the gamete to the sub-second generation (F2) material and Methods: The rat model of high-fat feeding (HFD) during pregnancy was established. The body weight and lipid metabolism of the F1 generation after normal feeding were observed, and then the F1 generation was used to mate with the normal sex rats and the high-fat children, and the HFD-F1 mice and the HFD-F1 mice were observed. The weight of each age group and the change of lipid metabolism in the F2 generation of the birth. The real-time PCR method is used to screen the imprinting gene related to the lipid metabolism in the F1 generation, the F2 generation liver and the F1 sperm to screen the maternal imprinting gene Igf2. And the methylation changes of the two imprinted genes in the F2 adult liver are respectively detected by the sulfite-modified sequencing method to explore the parent. The results showed that the body weight was significantly higher in the first 3 weeks of high-fat feeding. There was no significant difference between the two groups in the normal control group, but there was no significant difference between the two groups at 8 weeks. The results showed that the levels of TG, TC, HDL and LDL were significantly higher than that of control F1,8 and 12 weeks, but there was no significant difference between the two groups at 6 and 1. At the same time, there was a rise in LDL and a decrease in HDL. Although the F1 generation returned to normal diet and was subject to pregnancy There was no hyperlipoidemia before and during pregnancy, but the F2 generation of HFD-F1 (?) was shown to be a significant increase in the level of blood TG at 8 weeks,12 weeks and 6 months, and was accompanied by 12 and 6 months L the elevation of the dl; unlike this, the hfd -F1 (?) was not significantly different from the control group. We screened the gene gene related to lipid metabolism in the liver of F1 and F2, respectively, and found that the methylation of the maternal imprinting gene Igor and the parent-source imprinting gene Igf2r was continued high, while at F1 The two genes were demonstrated to be highly expressed on both the sperm and the F2 fetal liver, so we detected the imprinting gene Igor and Ig in the F2 liver f The results suggested that the HFD-F1 (?) was a low-methylation, Igf2r gene in 2 sites in the F2 adult liver. Conclusion: The high-fat diet in the parent pregnancy can cause the abnormal lipid metabolism of the first generation, and the abnormal lipid metabolism can be changed through the sub-generation.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R714.256
本文编号：2478590
[Abstract]:The first part of mother's hypertriglyceridemia induced a one-year high blood pressure by reprogramming the level of leptin in the offspring Objective: To confirm that the high triglyceride (TG) in the mother trimester of pregnancy can increase the incidence of adult high blood pressure in the offspring. To explore the role of leptin in the methylation of leptin gene Materials and Methods: The change of height, body weight and blood pressure of the individual with different birth weight in the pre-school period, the normal period and the adulthood, and the serum detection of leptin in some of the population Ping. At the same time,2687 pregnant women were surveyed with the basic information of blood lipid data and the birth of the offspring, and the levels of blood fat, fatty acid and leptin were detected by mother blood and umbilical cord blood. The model of hyperlipidemic rats during pregnancy was established by high-fat feeding. It is confirmed that high triglyceride blood is present in the late stage of the pregnancy The expression of the leptin gene and the wall thickness of the renal arterioles were detected by collecting the lymphocytes and/ or the adipose tissue and the kidney of each age group (fetal rat,3-week,8-week,6-month,1 year) of the offspring rats. degree. Detection of the expression and methylation of leptin in human umbilical cord blood and peripheral blood lymphocytes by a sulfite sequencing method Ping. The methylation of the leptin gene in the fetal and 3-week rats and the methylation of the 3-week rat lymphocytes were also detected by the same method. In-depth mechanism of bone marrow-derived mesenchymal stem cells (MSCs) isolated from the fetal rat The effect of high concentration of fatty acid on the expression and methylation of leptin in the process of adipocyte differentiation was studied by adding different concentrations of fatty acid to the process of adipocyte differentiation. Results: The level of serum leptin, which was continuously elevated from childhood to adulthood, was observed in the individual from childhood to adulthood, and the blood pressure in adulthood was significantly higher than that of the normal birth weight, and the incidence of hypertension in the 30-50 year of age was in the large group. The significant increase, although the body mass index (BMI) between the two groups was not significant The results showed that the serum triglyceride level (mTG) was significantly higher in the mothers with large and normal birth weight. In the control group, therefore, we calculated the mean value of the maternal blood TG value of 3.28 mM and then divided the data into the high-mother blood-lipid group (mTG3.28 mM) and the low-mother blood-lipid group (mTG3.28) according to the 2687 cases of the clinical investigation. The results showed that the level of serum leptin in the peripheral blood of the mothers of the high mTG group was increased significantly, and the level of leptin and the level of TG in the mother serum were significantly higher either at the time of birth or in the pre-school stage. The weight of the birth of the high-fat-fed animal was increased from 8 weeks to the control group in the same age, but the blood pressure was significantly higher than that in the control group. The level of leptin in each age group of the offspring of the high-fat mother was increased continuously, while the leptin gene of the adipose tissue and the lymphocytes of all age groups continued to be significant. High expression. The expression of lepitin gene in the neonatal and pre-school children born by the high TG mother was significantly higher than that of the control group, accompanied by a significant increase in the level of methylation. In the same time, the high expression of leptin was associated with the low methylation status of the fetal rat fat,3-week-old subcutaneous fat and visceral fat of the high-fat-fed mother, and the high expression and the low level of the lymphocyte letin in the 3-week-old offspring were also presented. The high concentration of fatty acid in the induction and differentiation of MSC in vitro can increase the expression of leptin gene and promote the high expression of the demethylase TET1, leading to the low leptin gene. Conclusion: The high-fat exposure of mother can influence its expression by modifying the methylation of leptin gene, so as to induce the adult height of the offspring. The second part: hypertriglyceridemia in the mother's pregnancy can increase the offspring's height by adjusting the leptin-mediated cholesterol metabolism pathway cholesterol Objective of the study of the risk of hypertriglyceridemia: to explore whether the level of leptin, which is caused by hypertriglyceridemia during pregnancy, is increased by regulating the expression of the key enzyme-cholesterol 7a-hydroxylase (CYP7-1) in cholesterol catabolism, thus increasing the generation of offspring. The risk of hypercholesteremia. Materials and Methods:250 cases of children born in our hospital from 2006 to 2007 were followed up by random telephone, and the serum of 49 pre-school children (3-6 years) who received a voluntary follow-up visit were collected. The levels of tin, blood lipid, and the like, and the mother's pregnancy were retrospectively investigated. The serum leptin and blood lipid level of 3-week-old offspring of high-fat children were further verified by high-fat-fed rat model during pregnancy, and the liver of 3-week-old offspring was detected by the chemiluminescence method. The blood lipid level of the homogenate of the dirty tissue was detected by Real-time PCR and Western blot. The expression of the key enzyme of cholesterol metabolism was studied. The expression of LEPR-JAK2-STAT3 was regulated by the mechanism of the in vitro culture of the liver cell line HepG2, and the expression of CYP7-1 was also regulated. STAT3 plays a regulating role; the immune co-precipitation (CHIP) test confirms that the transcription factor STAT3 can bind to the CYP7-1 gene The results showed that the serum leptin and cholesterol in the children with high mTG were significantly higher than those in the mTG group, and the serum leptin in the children was higher than that of the mTG group. There was a significant positive correlation between the level of cholesterol and the level of cholesterol. The level of serum leptin and cholesterol in high-fat-fed rats increased significantly, and the total cholesterol level in the liver tissue homogenate was significantly higher in the high-fat offspring than in the normal-feeding progeny group, accompanied by a cholesterol-degrading effect. The results of in vitro cell experiment show that the expression of LEPR, JAK2 and STAT3 in the pathway is up-regulated with the increase of leptin concentration, while the high concentration of lepti N The expression of CYP7-1 was downregulated. After the target of STAT3, the expression of CYP7-1 under the stimulation of leptin was no longer reduced, and the results of CHIP test further suggested that transcription factor STAT3 could bind to CYP7-1. Conclusion: The risk of high-cholesteremia in the children with hypertriglyceridemia during pregnancy is increased, and the high-fat-induced high-fat content of the offspring during pregnancy can be regulated by the LEPR-JAK2-STAT3 pathway. Expression of the key enzyme CYP7-1 gene in the third part: high-fat exposure during pregnancy induced Objective: To investigate the effect of high-fat diet on the lipid metabolism of the subgeneration (F1) in the parent mother during pregnancy, and to study the effect of the high-fat diet on the lipid metabolism of the offspring (F1). whether the adverse effect can be passed through the gamete to the sub-second generation (F2) material and Methods: The rat model of high-fat feeding (HFD) during pregnancy was established. The body weight and lipid metabolism of the F1 generation after normal feeding were observed, and then the F1 generation was used to mate with the normal sex rats and the high-fat children, and the HFD-F1 mice and the HFD-F1 mice were observed. The weight of each age group and the change of lipid metabolism in the F2 generation of the birth. The real-time PCR method is used to screen the imprinting gene related to the lipid metabolism in the F1 generation, the F2 generation liver and the F1 sperm to screen the maternal imprinting gene Igf2. And the methylation changes of the two imprinted genes in the F2 adult liver are respectively detected by the sulfite-modified sequencing method to explore the parent. The results showed that the body weight was significantly higher in the first 3 weeks of high-fat feeding. There was no significant difference between the two groups in the normal control group, but there was no significant difference between the two groups at 8 weeks. The results showed that the levels of TG, TC, HDL and LDL were significantly higher than that of control F1,8 and 12 weeks, but there was no significant difference between the two groups at 6 and 1. At the same time, there was a rise in LDL and a decrease in HDL. Although the F1 generation returned to normal diet and was subject to pregnancy There was no hyperlipoidemia before and during pregnancy, but the F2 generation of HFD-F1 (?) was shown to be a significant increase in the level of blood TG at 8 weeks,12 weeks and 6 months, and was accompanied by 12 and 6 months L the elevation of the dl; unlike this, the hfd -F1 (?) was not significantly different from the control group. We screened the gene gene related to lipid metabolism in the liver of F1 and F2, respectively, and found that the methylation of the maternal imprinting gene Igor and the parent-source imprinting gene Igf2r was continued high, while at F1 The two genes were demonstrated to be highly expressed on both the sperm and the F2 fetal liver, so we detected the imprinting gene Igor and Ig in the F2 liver f The results suggested that the HFD-F1 (?) was a low-methylation, Igf2r gene in 2 sites in the F2 adult liver. Conclusion: The high-fat diet in the parent pregnancy can cause the abnormal lipid metabolism of the first generation, and the abnormal lipid metabolism can be changed through the sub-generation.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R714.256
【共引文献】
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