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Background & Aims: Exposure to a range of elements, air pollution, and specific dietary components in pregnancy has variously been associated with gestational diabetes mellitus (GDM) risk or infant neurodevelopmental problems. We measured a range of pregnancy exposures in maternal hair and/or infant cord serum and tested their relationship to GDM and infant neurodevelopment., Methods: A total of 843 pregnant women (GDM = 224, Non-GDM = 619) were selected from the Complex Lipids in Mothers and Babies cohort study. Forty-eight elements in hair and cord serum were quantified using inductively coupled plasma-mass spectrometry analysis. Binary logistic regression was used to estimate the associations between hair element concentrations and GDM risk, while multiple linear regression was performed to analyze the relationship between hair/cord serum elements and air pollutants, diet exposures, and Bayley Scales of infant neurodevelopment at 12 months of age., Results: After adjusting for maternal age, BMI, and primiparity, we observed that fourteen elements in maternal hair were associated with a significantly increased risk of GDM, particularly Ta (OR = 9.49, 95% CI: 6.71, 13.42), Re (OR = 5.21, 95% CI: 3.84, 7.07), and Se (OR = 5.37, 95% CI: 3.48, 8.28). In the adjusted linear regression model, three elements (Rb, Er, and Tm) in maternal hair and infant cord serum were negatively associated with Mental Development Index scores. For dietary exposures, elements were positively associated with noodles (Nb), sweetened beverages (Rb), poultry (Cs), oils and condiments (Ca), and other seafood (Gd). In addition, air pollutants PM2.5 (LUR) and PM10 were negatively associated with Ta and Re in maternal hair., Conclusions: Our findings highlight the potential influence of maternal element exposure on GDM risk and infant neurodevelopment. We identified links between levels of these elements in both maternal hair and infant cord serum related to air pollutants and dietary factors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The leptin signalling pathway is important in metabolic health during pregnancy. However, few studies have investigated the determinants and extent of leptin receptor gene (LEPR) expression in the placenta, nor the relationship with infant health in early life. Here, we investigate the genetic and maternal in utero determinants of placental LEPR expression, and whether this expression is linked to anthropometric and inflammatory measures at birth in healthy newborns in the Barwon Infant Study., Methods: Placental LEPR expression was measured using RT-qPCR (n = 854 placentae). Associations between genetic variation in LEPR, maternal in utero factors, measures at birth and placental LEPR expression were assessed using multivariable linear regression modelling., Results: We found that the genotype at two intronic SNPs, rs9436301 and rs9436746, was independently associated with placental LEPR expression. Maternal pre-pregnancy body mass index, gestational diabetes mellitus, weight gain and smoking in pregnancy were not associated with LEPR expression. Placental LEPR expression was negatively associated with high sensitivity C-Reactive Protein in umbilical cord blood, which persisted after adjustment for potential confounders., Discussion: Overall, our findings suggest that genetic variation in LEPR plays a key role in regulating placental LEPR expression, which is in turn is associated with inflammatory markers in cord blood at birth. Further studies encompassing other aspects of leptin signalling are warranted to understand if these relationships are causal and have health implications., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Fetal sex influences placental function as well as maternal and fetal health, being an important factor to consider in pregnancy studies. However, fetal sex determination in the first trimester of pregnancy still faces some technical limitations. Here we describe an RT-qPCR technique to determine fetal sex based on X-inactive specific transcript (XIST) and DEAD-Box helicase 3 Y-linked (DDX3Y) gene expression. This method is straightforward, reliable, fast and applicable on both, placental tissue and primary cells., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Placental transfer of amino acids via amino acid transporters is essential for fetal growth. Little is known about the epigenetic regulation of amino acid transporters in placenta. This study investigates the DNA methylation status of amino acid transporters and their expression across gestation in human placenta., Methods: BeWo cells were treated with 5-aza-2'-deoxycytidine to inhibit methylation and assess the effects on amino acid transporter gene expression. The DNA methylation levels of amino acid transporter genes in human placenta were determined across gestation using DNA methylation array data. Placental amino acid transporter gene expression across gestation was also analysed using data from publically available Gene Expression Omnibus data sets. The expression levels of these transporters at term were established using RNA sequencing data., Results: Inhibition of DNA methylation in BeWo cells demonstrated that expression of specific amino acid transporters can be inversely associated with DNA methylation. Amino acid transporters expressed in term placenta generally showed low levels of promoter DNA methylation. Transporters with little or no expression in term placenta tended to be more highly methylated at gene promoter regions. The transporter genes SLC1A2, SLC1A3, SLC1A4, SLC7A5, SLC7A11 and SLC7A10 had significant changes in enhancer DNA methylation across gestation, as well as gene expression changes across gestation., Conclusion: This study implicates DNA methylation in the regulation of amino acid transporter gene expression. However, in human placenta, DNA methylation of these genes remains low across gestation and does not always play an obvious role in regulating gene expression, despite clear evidence for differential expression as gestation proceeds., (Copyright © 2017. Published by Elsevier Ltd.)

Epigenetic mechanisms, often defined as regulating gene activity independently of underlying DNA sequence, are crucial for healthy development. The sum total of epigenetic marks within a cell or tissue (the epigenome) is sensitive to environmental influence, and disruption of the epigenome in utero has been associated with adverse pregnancy outcomes. Not surprisingly, given its multifaceted functions and important role in regulating pregnancy outcome, the placenta shows unique epigenetic features. Interestingly however, many of these are only otherwise seen in human malignancy (the pseudomalignant placental epigenome). Epigenetic variation in the placenta is now emerging as a candidate mediator of environmental influence on placental functioning and a key regulator of pregnancy outcome. However, replication of findings is generally lacking, most likely due to small sample sizes and a lack of standardization of analytical approaches. Defining DNA methylation "signatures" in the placenta associated with maternal and fetal outcomes offers tremendous potential to improve pregnancy outcomes, but care must be taken in interpretation of findings. Future placental epigenetic research would do well to address the issues present in epigenetic epidemiology more generally, including careful consideration of sample size, potentially confounding factors, issues of tissue heterogeneity, reverse causation, and the role of genetics in modulating epigenetic profile. The importance of animal or in vitro models in establishing a functional role of epigenetic variation identified in human beings, which is key to establishing causation, should not be underestimated., (Copyright © 2015 Elsevier Inc. All rights reserved.)

As the primary interface between maternal and fetal circulations, the placenta is subject to a myriad of environmental exposures with the capacity to alter placental function and fetal development. Many of these effects are likely to be mediated by epigenetic ('above DNA') change, which is also in turn regulated by maternal and fetal genetic factors. Linking specific environmental exposures, genetic, and epigenetic variation to maternal and fetal outcomes may provide valuable mechanistic insights into the role of placental dysfunction in pregnancy-associated disease and later health. The complexities are manifold but are rapidly being overcome by technological advances and emerging analytical approaches. Although focussing on recent genome-scale and gene-specific DNA methylation studies in the human placenta, this review also discusses the potential of a future broader exploration of combined environmental, genetic and epigenomic approaches, encompassing higher order epigenetic modifications, for unravelling the molecular mechanisms underlying gene-environment interaction at the fetomaternal interface., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: There are multiple potential regulators of neonatal vitamin D status of environmental, genetic, and epigenetic origins. The relation between these factors and circulating neonatal vitamin D has yet to be fully characterized., Objective: The aim of this study was to examine the relative contribution of genetic factors, maternal circulating 25-hydroxyvitamin D [25(OH)D] concentrations, and the placental methylation level of the gene that encodes the primary catabolic enzyme of active vitamin D [25(OH)D-24-hydroxylase encoded by CYP24A1] to neonatal 25(OH)D concentrations., Design: We used the classical twin study design to determine the genetic contribution to neonatal 25(OH)D. A total of 86 twin pairs (32 monozygotic and 54 dizygotic twin pairs) were included in this study. Serum 25(OH)D was measured by using a 25(OH)D kit. CYP24A1 promoter DNA methylation was measured by means of matrix-assisted laser desorption time-of-flight mass spectrometry., Results: Maternal and neonatal 25(OH)D showed a strong association (R² = 0.19). Monozygotic and dizygotic within-pair serum 25(OH)D correlations were similar (R² = 0.71 and 0.67, respectively), which suggested no genetic effect. Placental CYP24A1 methylation did not show an association with maternal or neonatal 25(OH)D concentrations., Conclusions: Our results suggest that maternal circulating 25(OH)D is the most significant regulator of neonatal circulating 25(OH)D concentrations, with underlying genetic factors playing a limited role. The placental methylation of the CYP24A1 promoter appears subject to a genetic influence, although no evidence of a relation between the methylation level of this gene and circulating maternal or neonatal 25(OH)D was apparent.

The placenta has arisen relatively recently and is among the most rapidly evolving tissues in mammals. Several different placental barrier and structure types appear to have independently evolved common functional features. Specific patterns of gene expression that determine placental development in humans are predicted to be accompanied by specific profiles of epigenetic modification. However, the stratification of epigenetic modifications into those involved in conserved aspects of placental function, versus those involved in divergent placental features, has yet to begin. As a first step towards this goal, we have investigated the methylation status of a small number of gene-specific methylation events recently identified in human placenta, in a panel of placental tissue from baboon, marmoset, cow, cat, guinea pig and mouse. These represent disparate placental barrier types and structures. In this study we hypothesized that specific epigenetic markings may be associated with placental barrier type or function, independent of phylogeny. However, in contrast to our predictions, the majority of gene-specific methylation appears to track with phylogeny, independent of placental barrier type or other structural features. This suggests that despite the likelihood of epigenetic modification playing a role in the functioning and evolution of different placental subtypes, there is no evidence for an involvement of the gene-specific methylation profiles we have identified, in specifying these differences. Further studies, examining larger numbers of epigenetic modifications across phylogeny, are required to define the role of specific epigenetic modifications in the evolution of distinct placental structures., (Copyright 2010 Elsevier Ltd. All rights reserved.)

In a cohort of 593 long-term survivors of acute lymphocytic leukemia identified through the Children's Cancer Group (CCG), treatment abstracts were obtained and compared to protocol information on radiation therapy and intravenous chemotherapy. This was done in order to evaluate the actual compliance to protocol-specified treatment, and assess if protocol-specified doses can be used in studies of late effects of treatment. The compliance to protocol-specified type of treatment ranged between 95.3% (intrathecal methotrexate) and 98.6% (adriamycin) for chemotherapy, and between 94.1% (cranial radiation) and 97.0% (extended field radiation) for radiation. Concordance with the protocol-specified chemotherapy dose (+/- 25%) was 57.5% for adriamycin, 91.3% for daunomycin, and 48.5% for cyclophosphamide. When concordance was low, most patients received doses that were lower than expected. Concordance with chemotherapy was significantly lower for high-dose regimens than for low-dose regimens. Concordance with protocol-specified radiation dose (+/- 10%) was 87.4% for cranial radiation, 87.8% for spinal radiation, and 85.7% for extended field radiation. Concordance with treatment did not differ by gender, relapse status, or age at diagnosis. In this cohort of leukemia survivors, the validity of type of treatment was greater than the validity of dosage. Great care should be used when drawing conclusions about effects of treatment dosage. Although costly and time consuming, it appears that chart reviews are the most appropriate way to collect information about dose-related effects of therapy.