The placenta: phenotypic and epigenetic modifications induced by Assisted Reproductive Technologies throughout pregnancy

Abstract

Today, there is growing interest in the potential epigenetic risk related to assisted reproductive technologies (ART). Much evidence in the literature supports the hypothesis that adverse pregnancy outcomes linked to ART are associated with abnormal trophoblastic invasion. The aim of this review is to investigate the relationship between epigenetic dysregulation caused by ART and subsequent placental response. The dialogue between the endometrium and the embryo is a crucial step to achieve successful trophoblastic invasion, thus ensuring a non-complicated pregnancy and healthy offspring. However, as described in this review, ART could impair both actors involved in this dialogue. First, ART may induce epigenetic defects in the conceptus by modifying the embryo environment. Second, as a result of hormone treatments, ART may impair endometrial receptivity. In some cases, it results in embryonic growth arrest but, when the development of the embryo continues, the placenta could bring adaptive responses throughout pregnancy. Amongst the different mechanisms, epigenetics, especially thanks to a finely tuned network of imprinted genes stimulated by foetal signals, may modify nutrient transfer, placental growth and vascularization. If these coping mechanisms are overwhelmed, improper maternal-foetal exchanges occur, potentially leading to adverse pregnancy outcomes such as abortion, preeclampsia or intra-uterine growth restriction. But in most cases, successful placental adaptation enables normal progress of the pregnancy. Nevertheless, the risks induced by these modifications during pregnancy are not fully understood. Metabolic diseases later in life could be exacerbated through the memory of epigenetic adaptation mechanisms established during pregnancy. Thus, more research is still needed to better understand abnormal interactions between the embryo and the milieu in artificial conditions. As trophectoderm cells are in direct contact with the environment, they deserve to be studied in more detail. The ultimate goal of these studies will be to render ART protocols safer. Optimization of the environment will be the key to improving the dialogue between the endometrium and embryo, so as to ensure that placentation after ART is similar to that following natural conception.

Assessment of ‘one-step’ versus ‘sequential’ embryo culture conditions through embryonic genome methylation and hydroxymethylation changes

“…DNA methylation on cytosines (5-methylcytosine: 5meC) is an essential epigenetic modification that seems to be particularly affected by in vitro culture (Wright et al ., 2011) and to have an impact on the health of children born after ART, in particular through misregulation of imprinted genes (Fauque et al ., 2007; Choux et al ., 2015), leading to rare syndromes such as Beckwith–Wiedemann and Angelman (Manipalviratn et al ., 2009; Owen and Segars, 2009; Lazaraviciute et al ., 2015). In addition to its importance in imprinting, DNA methylation is involved in the regulation of many developmental processes such as parental imprinting, X-inactivation and control of endogenous retrotransposons (Watkins et al ., 2008b; Corry et al ., 2009).…”

Function and Hormonal Regulation of GATA3 in Human First Trimester Placentation

“…Notably, epigenetic changes have been found to play an important role in the regulation of placentation [18]. During pre-implantation embryo development, global DNA methylation reprogramming occurs, and both rodent and choriocarcinoma cell line studies have shown that specific patterns of methylation are important for normal placental function and that aberrations in methylation negatively affect placentation [19–21]. …”

In vitro fertilization placenta overgrowth in mice is associated with downregulation of the paternal imprinting gene H19

“…The placental epigenome plays a vital role that could constitute a major compensatory mechanism in the development and adaptive function to environmental stress caused by IVF (Choux et al, ; Decato et al, ). Future studies should focus on the epigenetic mechanisms underlying IVF‐induced regulation of the expression of the imprinted gene H19‐IGF2 as well as histone modification and lncRNA adjustment.…”

“…Future studies should focus on the epigenetic mechanisms underlying IVF‐induced regulation of the expression of the imprinted gene H19‐IGF2 as well as histone modification and lncRNA adjustment. Epigenetic regulation controls transcription at two levels: direct control of DNA through DNA methylation or hydroxymethylation and histone modification of proteins around which DNA is wrapped to constitute nucleosomes (Choux et al, ). We used quantitative BSP to evaluate the methylation status of the H19‐ICR region and found that the total methylation level at CpG dinucleotide sites was remarkably increased in the IVF group.…”