BACKGROUND Genomic imprinting is an epigenetic gene regulatory mechanism; disruption of this process during early embryonic development can have major consequences on both fetal and placental development. The periconceptional period and intrauterine life are crucial for determining long-term susceptibility to diseases. Treatments and procedures in assisted reproductive technologies (ART) and adverse in-utero environments may modify the methylation levels of genomic imprinting regions, including insulin-like growth factor 2 (IGF2)/H19, mesoderm-specific transcript (MEST), and paternally expressed gene 10 (PEG10), affecting the development of the fetus. ART, maternal psychological stress, and gestational exposures to chemicals are common stressors suspected to alter global epigenetic patterns including imprinted genes. OBJECTIVE AND RATIONALE Our objective is to highlight the effect of conception mode and maternal psychological stress on fetal development. Specifically, we monitor fetal programming, regulation of imprinted genes, fetal growth, and long-term disease risk, using the imprinted genes IGF2/H19, MEST, and PEG10 as examples. The possible role of environmental chemicals in genomic imprinting is also discussed. SEARCH METHODS A PubMed search of articles published mostly from 2005 to 2019 was conducted using search terms IGF2/H19, MEST, PEG10, imprinted genes, DNA methylation, gene expression, and imprinting disorders (IDs). Studies focusing on maternal prenatal stress, psychological well-being, environmental chemicals, ART, and placental/fetal development were evaluated and included in this review. OUTCOMES IGF2/H19, MEST, and PEG10 imprinted genes have a broad developmental effect on fetal growth and birth weight variation. Their disruption is linked to pregnancy complications, metabolic disorders, cognitive impairment, and cancer. Adverse early environment has a major impact on the developing fetus, affecting mostly growth, the structure, and subsequent function of the hypothalamic-pituitary-adrenal axis and neurodevelopment. Extensive evidence suggests that the gestational environment has an impact on epigenetic patterns including imprinting, which can lead to adverse long-term outcomes in the offspring. Environmental stressors such as maternal prenatal psychological stress have been found to associate with altered DNA methylation patterns in placenta and to affect fetal development. Studies conducted during the past decades have suggested that ART pregnancies are at a higher risk for a number of complications such as birth defects and IDs. ART procedures involve multiple steps that are conducted during critical windows for imprinting establishment and maintenance, necessitating long-term evaluation of children conceived through ART. Exposure to environmental chemicals can affect placental imprinting and fetal growth both in humans and in experimental animals. Therefore, their role in imprinting should be better elucidated, considering the ubiquitous exposure to these chemicals. WIDER IMPLICATIONS Dysregulation of imprinted genes is a plausible mechanism linking stressors such as maternal psychological stress, conception using ART, and chemical exposures with fetal growth. It is expected that a greater understanding of the role of imprinted genes and their regulation in fetal development will provide insights for clinical prevention and management of growth and IDs. In a broader context, evidence connecting impaired imprinted gene function to common diseases such as cancer is increasing. This implies early regulation of imprinting may enable control of long-term human health, reducing the burden of disease in the population in years to come.

中文翻译：

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宫内压力和受孕方式：对印迹基因调控，胎儿发育和未来健康的影响。

背景技术基因组印迹是一种表观遗传基因调控机制。在胚胎早期发育过程中破坏这一过程可能对胎儿和胎盘发育都产生重大影响。围产期和宫内生活对于确定疾病的长期易感性至关重要。在辅助生殖技术（ART）和不利的宫内环境中的治疗和程序可能会改变基因组印迹区域的甲基化水平，包括胰岛素样生长因子2（IGF2）/ H19，中胚层特异性转录本（MEST）和父本表达基因10（PEG10），影响胎儿的发育。ART，母亲的心理压力以及妊娠期接触化学物质是常见的应激源，被怀疑会改变包括标记基因在内的全球表观遗传模式。目的和理由我们的目的是强调受孕方式和母亲心理压力对胎儿发育的影响。具体来说，我们以印迹基因IGF2 / H19，MEST和PEG10为例，监测胎儿的程序设计，印迹基因的调控，胎儿生长和长期疾病风险。还讨论了环境化学物质在基因组印迹中的可能作用。搜索方法使用搜索词IGF2 / H19，MEST，PEG10，印迹基因，DNA甲基化，基因表达和印迹障碍（ID）对发表于2005年至2019年的文章进行PubMed搜索。评估了针对产妇产前压力，心理健康，环境化学物质，抗逆转录病毒疗法和胎盘/胎儿发育的研究，并将其纳入本评价。结果IGF2 / H19，MEST，和PEG10印迹基因对胎儿的生长和出生体重的变化具有广泛的发展作用。它们的破坏与妊娠并发症，代谢紊乱，认知障碍和癌症有关。不良的早期环境对发育中的胎儿有重大影响，主要影响下丘脑-垂体-肾上腺轴的生长，结构和随后的功能以及神经发育。大量证据表明，妊娠环境会对表观遗传模式（包括印迹）产生影响，这可能导致后代的长期不良结局。已发现环境压力因素，如产妇的产前心理压力与胎盘中DNA甲基化模式的改变有关，并影响胎儿的发育。在过去的几十年中进行的研究表明，ART妊娠发生许多并发症（如先天缺陷和身分证）的风险较高。ART程序涉及在印记建立和维护的关键窗口期间执行的多个步骤，因此需要对通过ART怀孕的孩子进行长期评估。暴露于环境化学物质可影响人和实验动物的胎盘印记和胎儿生长。因此，考虑到普遍存在于这些化学品中，应更好地阐明它们在印记中的作用。进一步的影响印迹基因的失调是将应激因素（如产妇的心理应激，使用抗逆转录病毒疗法的受孕以及化学暴露与胎儿生长）联系起来的一种合理机制。预期对印迹基因的作用及其在胎儿发育中的调控的更深入的了解将为临床预防和管理生长与IDs提供见识。在更广泛的背景下，将受损的印迹基因功能与常见疾病（例如癌症）联系起来的证据正在增加。这意味着对烙印的早期调节可以控制人类的长期健康，从而减轻今后几年人口疾病的负担。