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With the increasing maturity and widespread application of assisted reproductive technology (ART), more attention has been paid to the health outcomes of offspring following ART. It is well established that children born from ART treatment are at an increased risk of imprinting errors and imprinting disorders. The disturbances of genetic imprinting are attributed to the overlap of ART procedures and important epigenetic reprogramming events during the development of gametes and early embryos, but the detailed mechanisms are hitherto obscure. In this review, we summarized the DNA methylation-dependent and independent mechanisms that control the dynamic epigenetic regulation of imprinted genes throughout the life cycle of a mammal, including erasure, establishment, and maintenance. In addition, we systematically described the dysregulation of imprinted genes in embryos conceived through ART and discussed the corresponding underlying mechanisms according to findings in animal models. This work is conducive to evaluating and improving the safety of ART. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a toxic metal ubiquitous in the environment. In utero, Cd is inefficiently transported to the foetus but causes foetal growth restriction (FGR), likely through impairment of the placenta where Cd accumulates. However, the underlying molecular mechanisms are poorly understood. Cd can modulate the expression of imprinted genes, defined by their transcription from one parental allele, which play critical roles in placental and foetal growth. The expression of imprinted genes is governed by DNA methylation at Imprinting Control Regions (ICRs), which are susceptible to environmental perturbation. The imprinted gene Cdkn1c/CDKN1C is a major regulator of placental development, is implicated in FGR, and shows increased expression in response to Cd exposure in mice. Here, we use a hybrid mouse model of in utero Cd exposure to determine if the increase in placental Cdkn1c expression is caused by changes to ICR DNA methylation and loss of imprinting (LOI). Consistent with prior studies, Cd causes FGR and impacts placental structure and Cdkn1c expression at late gestation. Using polymorphisms to distinguish parental alleles, we demonstrate that increased Cdkn1c expression is not driven by changes to DNA methylation or LOI. We show that Cdkn1c is expressed primarily in the placental labyrinth which is proportionally increased in size in response to Cd. We conclude that the Cdassociated increase in Cdkn1c expression can be fully explained by alterations to placental structure. These results have implications for understanding mechanisms of Cd-induced placental dysfunction and, more broadly, for the study of FGR associated with increased Cdkn1c/CDKN1C expression. [ABSTRACT FROM AUTHOR]

Developmental exposure to environmental toxicants can induce transgenerational reproductive disease phenotypes through epigenetic mechanisms. We treated pregnant CD-1 (F0) mice with drinking water containing sodium arsenite (85 ppm) from days 8 to 18 of gestation. Male offspring were bred with untreated female mice until the F3 generation was produced. Our results revealed that F0 transient exposure to arsenic can cause decreased sperm quality and histological abnormalities in the F1 and F3. The overall methylation status of Igf2 DMR2 and H19 DMR was significantly lower in the arsenic-exposed group than that of the control group in both F1 and F3. The relative mRNA expression levels of Igf2 and H19 in arsenic-exposed males were significantly increased in both F1 and F3. This study indicates that ancestral exposure to arsenic may result in transgenerational inheritance of an impaired spermatogenesis phenotyping involving both epigenetic alterations and the abnormal expression of Igf2 and H19. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms such as genomic imprinting have a fundamental role in embryo and fetal development. Hence, we here studied expression levels of epigenetic modifiers and imprinted genes in cases of ididopathic spontaneous abortion (SA). Thirty-five placental samples and 35 matched fetal tissues from second trimester SA were analysed; including 16 controls (placental and fetal infections as the known cause of spontaneous abortion) and 19 idiopathic SA cases. Transcript levels of epigenetic regulators and imprinted genes were measured by qRT-PCR and methylation at imprinted genes was studied by bisulfite genomic sequencing and MS-MLPA. Global DNA hydroxymethylation (5-hmC) levels were measured by an ELISA-based assay. We observed an upregulation of TET2 and TET3 in placental samples from idiopathic SA cases; however, no significant difference in global 5-hmC levels was observed. On the contrary, in fetal tissues, TET3 was markedly downregulated in idiopathic SA, showing an opposite trend to that observed in placental tissue. IGF2 and CDKN1C were upregulated and MEST downregulated in placentas from idiopathic SA cases; concordantly, IGF2 was also upregulated in fetal tissues from idiopathic SA cases. Although not reaching statistical significance, an increase in methylation levels of MEST, KvDMR1 and H19 DMRs was observed in idiopathic SA cases, concordantly with the observed changes in expression. Our study reveals, for the first time, deregulation of epigenetic modifiers and imprinted genes in both placental and fetal tissues from idiopathic SA cases in the second trimester of pregnancy, indicating a critical role during pregnancy. [ABSTRACT FROM AUTHOR]

Excessive inflammation during pregnancy alters homeostatic mechanisms of the developing fetus and has been linked to adverse pregnancy outcomes. An anti-inflammatory diet could be a promising avenue to combat the pro-inflammatory state of pregnancy, particularly in obese women, but we lack mechanistic data linking this dietary pattern during pregnancy to inflammation and birth outcomes. In an ethnically diverse cohort of 1057 mother-child pairs, we estimated the relationships between dietary inflammatory potential [measured via the energy-adjusted dietary inflammatory index (E-DII™)] and birth outcomes overall, as well as by offspring sex and maternal pre-pregnancy body mass index (BMI). In a subset of women, we also explored associations between E-DII, circulating cytokines (n = 105), and offspring methylation (n = 338) as potential modulators of these relationships using linear regression. Adjusted regression models revealed that women with pro-inflammatory diets had elevated rates of preterm birth among female offspring [β = −0.22, standard error (SE) = 0.07,P<0.01], but not male offspring (β=0.09, SE = 0.06,P<0.12) (Pinteraction= 0.003). Similarly, we observed pro-inflammatory diets were associated with higher rates of caesarean delivery among obese women (β = 0.17, SE = 0.08,P= 0.03), but not among women with BMI <25 kg/m2(Pinteraction= 0.02). We observed consistent inverse associations between maternal inflammatory cytokine concentrations (IL-12, IL-17, IL-4, IL-6, and TNFα) and lower methylation at theMEG3regulatory sequence (P<0.05); however, results did not support the link between maternal E-DII and circulating cytokines. We replicate work by others on the association between maternal inflammatory diet and adverse pregnancy outcomes and provide the first empirical evidence supporting the inverse association between circulating cytokine concentrations and offspring methylation. [ABSTRACT FROM PUBLISHER]

Infertility affects one in 6 couples in developed nations, resulting in an increasing use of assisted reproductive technologies (ART). Both ART and subfertility appear to be linked to lower birth weight outcomes, setting infants up for poor long-term health. Prenatal growth is, in part, regulated via epigenetically-controlled imprinted genes in the placenta. Although differences in DNA methylation between ART and control infants have been found, it remains unclear whether these differences are due to the ART procedures or to the underlying parental subfertility and how these methylation differences affect imprinted gene expression. In this study, we examined the expression of 108 imprinted genes in placental tissues from infants born to subfertile parents (n = 79), matched naturally-conceived controls (n = 158), and infants conceived usingin vitrofertilization (IVF, n = 18). Forty-five genes were identified as having significantly different expression between the subfertile infants and controls, whereas no significant differences were identified between the IVF and control groups. The expression of 4 genes—IGF2, NAPIL5, PAX8-AS1, andTUBGCP5—was significantly downregulated in the IVF compared with the subfertile group. Three of the 45 genes significantly dysregulated between subfertile and control placentae—GRB10, NDN, andCD44—were found to have a significant positive correlation between expression and birth weight. Methylation levels for these 3 genes and 4 others—MKRN3, WRB, DHCR24, andCYR61—were significantly correlated with expression. Our findings indicate that epigenetic differences in placentas resulting from IVF pregnancies may be related to the underlying subfertility in parents using IVF rather than the IVF procedure itself. [ABSTRACT FROM PUBLISHER]

Objective: Genomic imprinting is an epigenetic phenomenon that results in differential expression of alleles, depending on their parental origin. The functional significance of DNA methylation in genomic imprinting has been widely investigated, and to date, approximately 100 imprinted genes have been identified in humans. Methods: To investigate whether the methylation status of these ‘known’ imprinting genes was associated with Parkinson’s disease (PD), we analyzed the methylation profiles of all ‘known’ imprinted genes using the Illumina 450K methylation chip. Samples were derived from mononuclear blood cells of 17 male Parkinson’s disease patients vs. 21 healthy male individuals and 12 discordant MZ twin pairs. Results: None of the annotated autosomal genes show changes in DNA methylation between PD individuals and healthy individuals. We further refined our analysis by evaluating the DNA methylation status of the maternally imprinted human gene encoding insulin-like growth factor 2 (IGF2)using bisulfite sequencing PCR (BSP) of DNA derived from 15 PD patients and 9 controls, taking into consideration different dosages of L-dopa. Conclusion: Our results demonstrated that methylation ofIGF2in PD patients was neither influenced by the dosage of L-dopa treatment nor by the disease itself. Thus, loss or disruption of imprinting in autosomal chromosomes does not seem to be relevant for the pathogenesis of the disease. [ABSTRACT FROM PUBLISHER]

Strong evidence suggests a potential link among epigenetics, microRNAs (miRNAs), and pregnancy complications. Much research still needs to be carried out to determine whether epigenetic factors are predictive in the pathogenesis of preeclampsia (PE), a life-threatening disease during pregnancy. Recently, the importance of maternal epigenetic features, including DNA methylation, histone modifications, epigenetically regulated miRNA, and the effect of imprinted or non-imprinted genes on trophoblast growth, invasion, as well as fetal development and hypertension in pregnancy, has been demonstrated in a series of articles. This article discusses the current evidence of this complicated network of miRNA and epigenetic factors as potential mechanisms that may underlie the theories of disease for PE. Translating these basic epigenetic findings to clinical practice could potentially serve as prognostic biomarkers for diagnosis in its early stages and could help in the development of prophylactic strategies. [ABSTRACT FROM AUTHOR]