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Hum Reprod Update. 2019 Nov 5;25(6):777-801. doi: 10.1093/humupd/dmz025.

In-utero stress and mode of conception: impact on regulation of imprinted genes, fetal development and future health.

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First Department of Obstetrics and Gynecology, Laboratory of Genetics, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia, 56403 Thessaloniki, Greece.
Karolinska Institutet, Department of Clinical Sciences, Intervention and Technology, Unit of Obstetrics and Gynecology, K57 Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden.
First Department of Obstetrics and Gynecology, Unit for Human Reproduction, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia, 56403 Thessaloniki, Greece.
Department of Biology, Laboratory of Biology, School of Health Sciences, University of Ioannina, Dourouti University Campus, 45110, Ioannina, Greece.



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.


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.


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.


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.


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.


IGF2/H19 ; MEST ; PEG10 ; ART; chemical exposures; fetal development; imprinting; imprinting disorders; maternal psychological stress


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