Epigenetic status in the offspring of spontaneous and assisted conception
Epigenetic status in the offspring of spontaneous and assisted conception
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DOI：
10.1093/humrep/deu094
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发表时间：
2014-07-01
影响因子：
6.1
通讯作者：
Haggarty, Paul
中科院分区：
文献类型：
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作者：
Whitelaw, Natalie;Bhattacharya, Siladitya;Haggarty, Paul
IVF（体外受精）和ICSI（胞质内单精子注射）后出生的儿童的颊细胞DNA甲基化与自然受孕的儿童不同吗？印迹基因，小核核糖核蛋白多肽N（SNRPN）的DNA甲基化在ICSI受孕的儿童中较高，无论受孕方法如何，不孕持续时间最长的妇女所生的儿童中较高。生育治疗与一系列不良产科结局，出生缺陷和长期后遗症的风险增加有关，但其生物学基础尚不清楚。越来越多的证据表明，表观遗传学可能在生育力低下以及生育力与健康之间的联系中发挥作用。在这项对2002年至2008年出生的儿童的回顾性队列研究中，我们测量了父系表达基因3（PEG 3）、胰岛素样生长因子II（IGF 2）、SNRPN、体外受精（n = 49）和胞浆内单精子注射（n = 20）后出生的儿童颊细胞DNA中的长散布核元件1（LINE 1）和胰岛素基因（INS），并将其与匹配的自然受孕组（n = 86）进行比较参与者从Aberdeen产妇和新生儿数据库中确定，IVF和ICSI妊娠与出生年份和分娩时母亲年龄的自发受孕妊娠相匹配。仅包括新鲜胚胎移植后的单胎妊娠。通过焦磷酸测序确定DNA甲基化。通过对协变量进行校正的回归分析来确定不育对后代DNA甲基化的影响。后代SNRPN甲基化与父母的生育治疗有关。这一效应仅限于使用ICSI受孕的儿童，在ICSI与自然受孕的比较中也很明显（1.03%; 95% CI 0.10，1.97; P = 0.031），ICSI vs标准IVF（1.13%; 95% CI 0.04，2.23; P = 0.043）和ICSI与标准IVF和自然受孕（1.05; 95% CI 0.15，1.94; P = 0.023）。在所有比较中，ICSI的使用与后代中较高水平的SNRPN甲基化相关。后代中较高水平的SNRPN甲基化也与父母不育的持续时间较长有关。在所有不孕病例中观察到这一点（每年0.18%的不孕症; 95% CI 0.02，0.33; P = 0.026），排除ICSI病例后（每年0.21%的不孕症; 95% CI 0.04，0.37; P = 0.017）。从出生到7岁，随着年龄的增长，LINE 1甲基化水平显著增加（每年0.77%; 95%CI 0.49，1.05; P < 0.001）。INS基因的甲基化在同一时期显著降低（每年-0.46%; 95% CI-0.89，-0.03; P = 0.035）。没有证据表明印记基因内的甲基化在生命的前7年发生了变化。ICSI样本量有限，但组经过精心选择和良好匹配，SNRPN结果在不同结局中是一致的。这项研究的结果为表观遗传学，特别是印记在生育中的作用提供了支持。这些具体的变化表明生育治疗对后代健康和生育能力可能产生的长期影响。作者报告说，这项工作没有利益冲突。资助由阿伯丁大学和苏格兰政府提供。不适用。
Is DNA methylation in buccal cell DNA from children born following IVF (in vitro fertilization) and ICSI (intra-cytoplasmic sperm injection) different from that of spontaneously conceived children?DNA methylation in the imprinted gene, small nuclear ribonucleoprotein polypeptide N (SNRPN), was higher in children conceived by ICSI and in those born to women with the longest duration of infertility regardless of the method of conception.Fertility treatment is associated with a small but significant increase in the risk of a range of adverse obstetric outcomes, birth defects and longer term sequelae, but the biological basis for this is unknown. A growing evidence base suggests that epigenetics may play a role in subfertility and the link between fertility and health.In this retrospective cohort study of children born between 2002 and 2008, we measured DNA methylation in paternally expressed gene 3 (PEG3), insulin-like growth factor II (IGF2), SNRPN, long interspersed nuclear element 1 (LINE1) and the insulin gene (INS) in buccal cell DNA from children born following IVF (n = 49) and ICSI (n = 20) and compared them with a matched spontaneous conception group (n = 86).Participants were identified from the Aberdeen Maternity and Neonatal Databank and IVF and ICSI pregnancies were matched to spontaneous conception pregnancies on year of birth and maternal age at delivery. Only singleton pregnancies following fresh embryo transfer were included. DNA methylation was determined by pyrosequencing. Regression with adjustment for covariates was used to determine the effect of infertility on offspring DNA methylation.SNRPN methylation in the offspring was linked to fertility treatment in the parents. This effect was specific to children conceived using ICSI and was apparent in the comparison of ICSI versus spontaneous conception (1.03%; 95% CI 0.10, 1.97; P = 0.031), ICSI versus standard IVF (1.13%; 95% CI 0.04, 2.23; P = 0.043) and ICSI versus standard IVF and spontaneous conception (1.05; 95% CI 0.15, 1.94; P = 0.023). In all comparisons, the use of ICSI was associated with a higher level of SNRPN methylation in the offspring. A higher level of SNRPN methylation in the offspring was also associated with a longer duration of infertility in the parents. This was observed in all cases of infertility (0.18% per year of infertility; 95% CI 0.02, 0.33; P = 0.026) and after excluding ICSI cases (0.21% per year of infertility; 95% CI 0.04, 0.37; P = 0.017). There was a significant increase in the level of LINE1 methylation with age between birth and 7 years (0.77% per year; 95% CI 0.49, 1.05; P < 0.001). Methylation in the INS gene decreased significantly over the same period (-0.46% per year; 95% CI -0.89, -0.03; P = 0.035). There was no evidence from this cross-sectional data that methylation within the imprinted genes changed over the first 7 years of life.The ICSI sample size was limited but the groups were carefully selected and well matched and the SNRPN findings were consistent across different outcomes.The results of this study provide support for a role for epigenetics, and imprinting in particular, in fertility. The specific changes point to possible long-term consequences of fertility treatment for the health and fertility of future generations.The authors report no conflict of interest in relation to this work. Funding was provided by the University of Aberdeen and the Scottish Government.Not applicable.