摘要
第一部分ART小鼠睾丸组织基因表达改变及跨代传递研究
已有的研究报告表明通过卵胞浆内单精子注射(intracytoplasmic sperm injection, ICSI)等辅助生殖技术(assisted reproductive techniques,ART)出生的男性后代,存在生殖道畸形发生率增加、精液质量下降和生殖功能相关基因表达异常等改变。然而由于遗传背景和生活环境的差异、加上伦理法律的限制,利用人类临床资料很难明确各项ART操作对男性生殖健康的影响。故此我们利用近交系小鼠,分别建立控制性超促排卵(controlled ovarian hyperstimulation, COH)、体外受精(in vitro fertilization and embryo-transfer, IVF-ET)和ICSI动物模型,对新生ART小鼠睾丸组织的基因的表达做进一步分析。
首先以自然出生小鼠为对照,应用表达芯片对通过ICSI受精出生的新生小鼠睾丸组织基因表达谱进行了分析。在芯片筛出的差异基因中,聚焦与男性生殖健康相关的8个非印记基因(Dmc1、Prok2、Rec8、Rhox5、Spol1、Adcyaplr1、 Amh和Pdgfra)及6个父源表达的印记基因(Igf2、Kcnqlot1、Mest、Peg3、Plagl1和Snrpn),应用RT-PCR检测这些基因在COH、IVF、ICSI出生成年小鼠(F1代),及其与自然出生小鼠交配出生的ART F2代小鼠睾丸组织中的表达；利用焦磷酸测序等检测F1代和-F2代小鼠睾丸中印记基因差异甲基化区域的甲基化修饰状态。
结果显示：(1)对于ICSI新生小鼠中表达下调的男性生殖健康相关的8个非印记基因,其差异可持续到成年F1代小鼠,而在新生鼠中表达上调的基因在成年到恢复止常的表达水平。6个父源表达的印记基因中印记基因Kcnqlot1、Mest、 Peg3、Plagll和Snrpn在ICSI成年F1代小鼠睾丸组织中表现出低表达和高甲基化。IVF成年小鼠的基因表达和甲基修饰改变与ICSI类似。(2)自然妊娠、COH、IVF和ICSIFl代小鼠之间还进行两两比较,分析不同ART处理对子代睾丸基因表达的影响,结果显示超促排卵、体外胚胎和ICSI机械刺激在不同程度上都可以影响睾丸基因表达水平。其中体外培养和机械刺激是造成父源印记基因表达下调的主要原因。对于非印记基因的表达下调,三个因素具有累加效应。(3)ICSI和IVF F1代小鼠中存在的印记基因表达和修饰改变,多数在F2代小鼠的睾丸组织中仍然可见。ART F1代存在的非印记基因表达改变多数在ICSI F2代仍可见,然而在IVF F2中已恢复正常。
结论：ICSI操作引起的小鼠睾丸基因表达改变,部分可延续到成年小鼠,其中成年小鼠睾丸间质和支持细胞的基因表达改变可能更为明显。超促排卵、体外培养和ICSI机械刺激等ART操作可在不同程度上影响出生小鼠睾丸基因表达。ART操作引起的小鼠睾丸基因表达改变机理涉及基因甲基化表观遗传修饰,并且睾丸基因表达和甲基化修饰改变可跨代传递,尤以ICSI为著。
第二部分ART雄性小鼠脂肪酸代谢的变化及机理研究
作为三大代谢之一,脂类代谢在宫内胎儿生长发育中作用重要。大量临床研究指出行辅助生殖技术(assisted reproductive techniques,ART)出生子代存在出生体重异常的现象,同时对ART受孕分娩胎盘的观察表明,此类妊娠易发胎盘形状和重量异常,可能影响胎盘脂类代谢,限制母婴间甾类激素的传递,改变胎儿正常的脂类代谢过程。本课题组前期研究发现ART新生雄性小鼠存在出生高体重,因此在第二部分继续探讨ART男性子代的健康状况,并将重点放在ART雄性后代脂肪酸代谢上。此外,在这部分中还将就ART小鼠脂肪酸代谢改变的机理做初步探索。
首先利用已建立的控制性超促排卵(controlled ovarian hyperstimulation,COH)、体外受精(in vitro fertilization and embryo-transfer, IVF-ET)和卵胞浆内单精子注射(intracytoplasmic sperm injection, ICSI)小鼠模型,对出生成年和老年雄性小鼠肝脏和脂肪组织中的脂肪酸组成、脂肪酸合成和分解代谢酶类相关基因进行了检测,并通过脂肪酸组成相关性分析探讨脂肪酸代谢相关酶的活性对脂肪酸组成的影响。其次,用两个剂量的促性腺激素对小鼠进行超排处理,检测胚胎的得率、脂类的分布和含量、脂肪酸组成以及甘油三脂代谢相关酶类的表达。同时检测促排组血清孕酮及卵巢胆固醇含量,分析其对胚胎脂代谢变化的影响。
结果发现：(1)与对照组-自然妊娠出生小鼠相比,三类ART小鼠的脂肪组织和肝脏组织的脂肪酸组成差异明显。各ART成年小鼠脂肪组织SFAs和MUFAs含量增加,PUFAs含量减少,而三类ART成年小鼠肝脏组织脂肪酸组成变化不尽相同。并且上述差异随小鼠年龄增加而改变。(2)脂肪酸代谢相关酶的活性和表达不仅在各组之间发生变化,而且随年龄的增长也有所改变。通过相关性分析发现脂肪酸代谢相关酶可能是通过调节肝脏中C16：0和脂肪组织中C18：0的含量影响脂肪酸的组成。在脂肪组织中无论是成年还是老年三个ART组中脂肪酸合成相关基因的表达水平变化都是一致的,而且脂肪酸合成相关基因的表达在自然妊娠组随年龄增长而增加,在三个ART组随年龄增长而降低。(3)胚胎中出现促性腺激素依赖性的脂类聚集、脂肪酸合成下降以及激素剂量依赖性的脂肪酸组成的改变。
结论：ART过程可改变成年雄性小鼠脂肪和肝脏组织的多种脂肪酸含量,影响相关调节酶类的表达。脂肪酸组成的变化可能与ART诱导脂代谢相关酶的活性和基因表达有关的改变相关。COH、IVF和ICSI小鼠脂肪组织中SFAs、MUFAs和PUFAs的含量以及有关调节基因的表达改变总趋势相同,提示促性腺激素对卵巢的刺激,可能是ART小鼠脂肪酸代谢改变的重要因素。ART过程对子代脂肪酸代谢的影响可能发生于卵母细胞成熟和胚胎发育早期。
Part I The persistency and intergenerational transmission of differentially expressed genes in the testes of ART mice
Worse reproductive health in the men born through intracytoplasmic sperm injection (ICSI) or other assisted reproductive techniques (ART) has been reported in some studies, such as hypospadias, reduced serum testosterone level, and lower semen quality. However, because of the interference of genetic and many environmental factors, it is difficult to identify whether ICSI methods affect male reproductive health based on clinical human data. Therefore, we established mouse ART models using inbred mice, including controlled ovarian hyperstimulation (COH), in vitro fertilization (IVF) and ICSI mice. Semen quality, serum testosterone and histological analysis of testes were done but no significant changes were shown in our previous studies. In this study, the gene expressions in testes were analyzed in ART mice.
The gene expression profiles were analysed in the testis of both ICSI and naturally conceived (NC) newborn F1mice using micro-array analysis. Among the differentially expressed genes, we focused on the expression of8male (Dmcl, Prok2, Rec8, Rhox5, Spol1, Adcyaplr1, Amh and Pdgfra) reproduction-related non-imprinted genes and6paternally expressed imprinted genes (Igf2, Kcnqlot1, Plagl1, Snrpn, Peg3and Mest). Quantitative real time RT-PCR (qRT-PCR) was used to analyse the expression of these genes in mouse testes of adult F1and F2generations. Pyrosequencing was used to analyse the methylation level of paternally expressed imprinted genes.
Our results showed that (1) For the8male reproduction-related non-imprinted genes, only down-regulated genes in newborn mice retained their differential expression pattern in adult F1generation, these genes were also down-regulated in IVF F1generation. Kcnqlot1, Plagl1, Snrpn, Peg3and Mest showed lower expression and higher methylation level in ICSI group than naturally conceived (NC) group, and the same changes were also shown in IVF mice. Compared with NC group, the changes on gene expression and DNA methylation level in IVF group was similar to that in ICSI group (2) Comparison between NC, COH, IVF and ICSI mice was done to analyze the effect of superovulation, in vitro culture and mechanical stimulation on the gene expression of testes. The down regulation of paternal expressed imprinted genes was mainly resulted from in vitro culture and mechanical stimulation. These three factors had an accumulative effect on the down regulation of male reproduction-related non-imprinted genes.(2) The differences of imprinted genes in ART F1mice were mostly observed in F2generation. The expression alteration of non-imprinted genes in ART Fl generation was mostly found in ICSI F2generations, but not in IVF F2generations.
Conclusion:ICSI treatment can induce the alteration of differential gene expression in testes of offspring. The differential expression of genes in ICSI newborn mice can be persistent to adulthood, especially the changes in somatic cell of testis. Superovulation, in vitro culture and mechanical stimulation by ICSI were to some extent in charge of the differences of gene expression in testes. The alteration of DNA methylation modification was associated with the gene expressed difference in the testis of ART mice. ART treatments could induce the intergenerational transmission of differential gens expression, especially in ICSI group.
Part II Alteration of fatty acid metabolism in ART male mice and the mechanism involved
Lipid metabolism plays an important role in the whole process of pregnancy. Pathological abnormalities of assisted reproductive technology (ART) placentas have also been described, including abnormal placental shape, abnormal umbilical cord insertion and increased placental weights. Meanwhile, ART-induced impairment of placental steroid metabolism and restricted delivery of steroid hormones from mother to fetus have been reported. Our previous studies found a higher birth weight in ART mice. Therefore, we continued the topic of the health of ART male offspring and focused on the fatty acid metabolism in the second part. Moreover, the association between hormone and lipid metabolism or body weight is generally accepted, and the effect of superovulation on early embryos were also analyzed in this part to find the probable causes of gonadotropin induced abnormal lipid metabolism in offspring.
Firstly we measured the fatty acid composition and the gene expression of lipogenesis and lipolysis-related enzymes in the liver and adipose tissue male mice produced by controlled ovarian hyperstimulation (COH), in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). The effect of the activities of fatty acid metabolism-related enzymes on fatty acid composition was estimated using the correlation analysis. Secondly, the mice were superovulated with two doses of gonadotropin, and the fertilization rate, lipid content and distribution, fatty acid composition and the expression of the triglyceride metabolism-related genes in embryos was analyzed. Moreover, the content of ovarian cholesterol and serum progesterone were also detected to analyze their effect on lipid metabolism of embryos.
Our results showed that (1) The significant alteration in the liver and adipose tissue compared to naturally conceived (NC) mice. Compared with the NC mice, ART mice have significantly lower level of Polyunsaturated fatty acids (PUFAs) and higher level of Saturated fatty acids (SFAs) and Monounsaturated fatty acids (MUFAs), while the alteration of fatty acid profile in the liver of ART mice was much more complex. The difference of fatty acid composition between the four groups of mice varied with age.(2)Using correlation analysis, we found lipid metabolism-related enzymes may influence fatty acid composition by regulating the content of C16:0and C18:0in liver and adipose tissue respectively. Compared with NC group, the expressions of lipogenic and lipolytic genes altered in ART groups, and the expressed changes of these genes with age were different between ART and NC group. The expression of fatty acid synthesis genes in ART groups showed the same changing trend compared with NC group in adipose tissue of both adult and old mice.(3) Gonadotropin increased lipid accumulation and decreased fatty acid synthesis in a dose-dependent manner, and the changes of fatty acid composition were also shown in gonadotropin-induced embryos.
These results indicated that ART treatments might have effect on the fatty acid composition and the expression of fatty acid metabolism-related genes in adipose tissue and liver of male offspring. The alteration of fatty acid composition was associated with ART induced alterations of activities and expressions of fatty acid metabolism-related enzymes. The changing trend of SFAs, MUFAs, PUFAs and the expression of fatty acid synthesis genes was consistent in adipose tissue of COH, IVF and ICSI mice, which suggested the effect of gonadotropin might be an key factor in the abnormal fatty acid metabolism of ART offspring. The effect of gonadotropin on lipid metabolism in offspring might be originated from the early embryo development.
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