Pre-pregnancy BMI-associated miRNA and mRNA expression signatures in the placenta highlight a sexually-dimorphic response to maternal underweight status.
Ontology highlight
ABSTRACT:
SUBMITTER: Clark J
PROVIDER: S-EPMC8333418 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundFetal sex and placental development impact pregnancy outcomes and fetal-maternal health, but the critical timepoint of placenta establishment in first trimester is understudied in human pregnancies.MethodsPregnant subjects were recruited in late first trimester (weeks 10-14) at time of chorionic villus sampling, a prenatal diagnostic test. Leftover placenta tissue was collected and stored until birth outcomes were known, then DNA and RNA were isolated from singleton, normal karyotype pregnancies resulting in live births. DNA methylation was measured with the Illumina Infinium MethylationEPIC BeadChip array (n = 56). Differential methylation analysis compared 25 females versus 31 males using a generalized linear model on 743,461 autosomal probes. Gene expression sex differences were analyzed with RNA-sequencing (n = 74). An integrated analysis was performed using linear regression to correlate gene expression and DNA methylation in 51 overlapping placentas.ResultsMethylation analysis identified 151 differentially methylated probes (DMPs) significant at false discovery rate < 0.05, including 89 (59%) hypermethylated in females. Probe cg17612569 (GABPA, ATP5J) was the most significant CpG site, hypermethylated in males. There were 11 differentially methylated regions affected by fetal sex, with transcription factors ZNF300 and ZNF311 most significantly hypermethylated in males and females, respectively. RNA-sequencing identified 152 genes significantly sexually dimorphic at false discovery rate < 0.05. The 151 DMPs were associated with 18 genes with gene downregulation (P < 0.05) in the direction of hypermethylation, including 2 genes significant at false discovery rate < 0.05 (ZNF300 and CUB and Sushi multiple domains 1, CSMD1). Both genes, as well as Family With Sequence Similarity 228 Member A (FAM228A), showed significant correlation between DNA methylation and sexually dimorphic gene expression, though FAM228A DNA methylation was less sexually dimorphic. Comparison with other sex differences studies found that cg17612569 is male-hypermethylated across gestation in placenta and in human blood up to adulthood.ConclusionsOverall, sex dimorphic differential methylation with associated differential gene expression in the first trimester placenta is small, but there remain significant genes that may be regulated through methylation leading to differences in the first trimester placenta.
| S-EPMC11328442 | biostudies-literature
Project description:BackgroundHealth outcomes among children born prematurely are known to be sexually dimorphic, with male infants often more affected, yet the mechanism behind this observation is not clear. CpG methylation levels in the placenta and blood also differ by sex and are associated with adverse health outcomes. We contrasted CpG methylation levels in the placenta and neonatal blood (n = 358) from the Extremely Low Gestational Age Newborn (ELGAN) cohort based on the EPIC array, which assays over 850,000 CpG sites across the epigenome. Sex-specific epigenome-wide association analyses were conducted for the placenta and neonatal blood samples independently, and the results were compared to determine tissue-specific differences between the methylation patterns in males and females. All models were adjusted for cell type heterogeneity. Enrichment pathway analysis was performed to identify the biological functions of genes related to the sexually dimorphic CpG sites.ResultsApproximately 11,500 CpG sites were differentially methylated in relation to sex. Of these, 5949 were placenta-specific and 5361 were blood-specific, with only 233 CpG sites overlapping in both tissues. For placenta-specific CpG sites, 90% were hypermethylated in males. For blood-specific CpG sites, 95% were hypermethylated in females. In the placenta, keratinocyte differentiation biological pathways were enriched among the differentially methylated genes. No enrichment pathways were observed for blood.ConclusionsDistinct methylation patterns were observed between male and female children born extremely premature, and keratinocyte differentiation pathways were enriched in the placenta. These findings provide new insights into the epigenetic mechanisms underlying sexually dimorphic health outcomes among extremely premature infants.
| S-EPMC10464100 | biostudies-literature
Project description:Autism spectrum disorder (ASD) is sexually dimorphic in brain structure, genetics, and behaviors. In studies of brain tissue, the age of the population is clearly a factor in interpreting study outcome, yet sex is rarely considered. To begin to address this issue, we extend our previously published microarray analyses to examine expression of small noncoding RNAs (sncRNAs), including microRNAs (miRNAs), in ASD and in the control temporal cortex in males and females. Predicted miRNA targets were identified as well as the pathways they overpopulate.After considering age, sexual dimorphism in ASD sncRNA expression persists in the temporal cortex and in the patterning that distinguishes regions. Among the sexually dimorphic miRNAs are miR-219 and miR-338, which promote oligodendrocyte differentiation, miR-125, implicated in neuronal differentiation, and miR-488, implicated in anxiety. Putative miRNA targets are significantly over-represented in immune and nervous system pathways in both sexes, consistent with previous mRNA studies. Even for common pathways, the specific target mRNAs are often sexually dimorphic. For example, both male and female target genes significantly populate the Axonal Guidance Signaling pathway, yet less than a third of the targets are common to both sexes.Our findings of sexual dimorphism in sncRNA levels underscore the importance of considering sex, in addition to age, when interpreting molecular findings on ASD brain.
| S-EPMC5294827 | biostudies-other
Project description:Diet during pregnancy influences the future health of a woman's offspring, with outcomes differing depending on the child's sex. Because the placenta buffers the fetus from the mother, we examined the impact of diet and fetal sex on placental gene expression in mice fed either a very-high-fat, low-fat, chow diet of intermediate caloric density. At day 12.5 of pregnancy, placental RNA was extracted and analyzed by microarray. The expression of 1,972 genes was changed more than 2-fold (P < 0.05) in comparisons across diet in at least one of the three groups. Female placentae demonstrated more striking alterations in gene expression in response to maternal diet than male placentae. Notably, each diet provided a distinctive signature of sexually dimorphic genes, with expression generally higher in genes (651 out of 700) from female placentae than those from male placentae. Several genes normally considered as characteristic of kidney function were affected by diet, including genes regulating ion balance and chemoreception. The placenta also expressed most of the known olfactory receptor genes (Olfr), which may allow the placenta to sense odorant molecules and other minor dietary components, with transcript levels of many of these genes influenced by diet and fetal sex. In conclusion, gene expression in the murine placenta is adaptive and shaped by maternal diet. It also exhibits pronounced sexual dimorphism, with placentae of females more sensitive to nutritional perturbations than placentae of males.
| S-EPMC2851754 | biostudies-literature
Project description:The aims were to investigate the association of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with breastfeeding (BF) duration and BF pattern at 3 months of age.This was a prospective cohort study of 4231 children who were enrolled at birth and were followed-up at 3, 12, 24 and 48 months of age to gather information on maternal and offspring characteristics including BF patterns and BF duration. Maternal pre-pregnancy BMI was categorized according to the WHO classification and GWG according to the 2009 Institute of Medicine recommendations. Cox's proportional hazards model was used to assess whether pre-pregnancy BMI and GWG were associated with BF and exclusive breastfeeding (EBF) duration. Predicted probabilities of BF patterns at 3 months were estimated by multinomial logistic regression.Information on BF was available to 4011 infants. The total BF and EBF median durations were 7.0 months and 1.5 months, respectively. There were no differences in duration of any BF or EBF according to pre-pregnancy BMI or GWG categories. There was an increased predicted probability for weaning before the age of 3 months among infants from obese women, compared with those from mothers with normal pre-pregnancy BMI, with margins adjusted predictions of 0.36 (95% confidence interval (CI) 0.31-0.41) and 0.23 (95% CI 0.21-0.25), respectively.Infants from pre-pregnancy overweight/obese mothers presented higher probability of early weaning compared with infants from normal-weight mothers. Obese/overweight pregnant women need supplementary guidance about BF benefits to infant health during prenatal and postnatal care.
| S-EPMC4827014 | biostudies-other
Project description:IntroductionObesity is a major clinical problem in obstetrics being associated with adverse pregnancy outcomes and fetal programming. Brain derived neurotrophic factor (BDNF), a validated miR-210 target, is necessary for placental development, fetal growth, glucose metabolism, and energy homeostasis. Plasma BDNF levels are reduced in obese individuals; however, placental BDNF has yet to be studied in the context of maternal obesity. In this study, we investigated the effect of maternal obesity and sexual dimorphism on placental BDNF signaling.MethodsBDNF signaling was measured in placentas from lean (pre-pregnancy BMI < 25) and obese (pre-pregnancy BMI>30) women at term without medical complications that delivered via cesarean section without labor. MiRNA-210, BDNF mRNA, proBDNF, and mature BDNF were measured by RT - PCR, ELISA, and Western blot. Downstream signaling via TRKB (BDNF receptor) was measured using Western blot.ResultsMaternal obesity was associated with increased miRNA-210 and decreased BDNF mRNA in placentas from female fetuses, and decreased proBDNF in placentas from male fetuses. We also identified decreased mature BDNF in placentas from male fetuses when compared to female fetuses. Mir-210 expression was negatively correlated with mature BDNF protein. TRKB phosphorylated at tyrosine 817, not tyrosine 515, was increased in placentas from obese women. Maternal obesity was associated with increased phosphorylation of MAPK p38 in placentas from male fetuses, but not phosphorylation of ERK p42/44.DiscussionBDNF regulation is complex and highly regulated. Pre-pregnancy/early maternal obesity adversely affects BDNF/TRKB signaling in the placenta in a sexually dimorphic manner. These data collectively suggest that induction of placental TRKB signaling could ameliorate the placental OB phenotype, thus improving perinatal outcome.
| S-EPMC5193148 | biostudies-literature
Project description:In the peripheral nerve, mechanosensitive axons are insulated by myelin, a multilamellar membrane formed by Schwann cells. Here, we offer first evidence that a myelin degradation product induces mechanical hypersensitivity and global transcriptomics changes in a sex-specific manner. Focusing on downstream signaling events of the functionally active 84-104 myelin basic protein (MBP(84-104)) fragment released after nerve injury, we demonstrate that exposing the sciatic nerve to MBP(84-104) via endoneurial injection produces robust mechanical hypersensitivity in female, but not in male, mice. RNA-seq and systems biology analysis revealed a striking sexual dimorphism in molecular signatures of the dorsal root ganglia (DRG) and spinal cord response, not observed at the nerve injection site. Mechanistically, intra-sciatic MBP(84-104) induced phospholipase C (PLC)-driven (females) and phosphoinositide 3-kinase-driven (males) phospholipid metabolism (tier 1). PLC/inositol trisphosphate receptor (IP3R) and estrogen receptor co-regulation in spinal cord yielded Ca2+-dependent nociceptive signaling induction in females that was suppressed in males (tier 2). IP3R inactivation by intrathecal xestospongin C attenuated the female-specific hypersensitivity induced by MBP(84-104). According to sustained sensitization in tiers 1 and 2, T cell-related signaling spreads to the DRG and spinal cord in females, but remains localized to the sciatic nerve in males (tier 3). These results are consistent with our previous finding that MBP(84-104)-induced pain is T cell-dependent. In summary, an autoantigenic peptide endogenously released in nerve injury triggers multisite, sex-specific transcriptome changes, leading to neuropathic pain only in female mice. MBP(84-104) acts through sustained co-activation of metabolic, estrogen receptor-mediated nociceptive, and autoimmune signaling programs.
| S-EPMC7397096 | biostudies-literature
Project description:Neonatal adiposity has many determinants and may be a risk factor for future obesity. Epigenetic regulation of metabolically important genes is a potential contributor.The objective of the study is to determine whether methylation changes in the LEP gene in cord blood DNA are impacted by the maternal environment or affect neonatal adiposity measures.A cross-sectional study of 114 full-term neonates born to healthy mothers with normal glucose tolerance was performed. Cord blood was assayed for leptin and genome-wide DNA methylation profiles via the Illumina 450K platform. Neonatal body composition was measured by air displacement plethysmography. Multivariate linear regression models and semi-partial correlation coefficients were used to analyze associations. False discovery rate was estimated to account for multiple comparisons.Maternal pre-pregnancy BMI was associated with decreased methylation at five CpG sites near the LEP transcription start site in an adjusted model (false discovery rate <0.022 for each site). The association between maternal BMI and cord blood leptin approached significance (r?=?0.18, p?=?0.054). Cord blood leptin was positively correlated with neonatal adiposity measures including birth weight (r?=?0.45, p?<?0.001), fat mass (r?=?0.47, p?<?0.001) and percent body fat (r?=?0.44, p?<?0.001).Maternal pre-pregnancy BMI is strongly associated with decreased cord blood LEP gene methylation and may mediate the well-known association between maternal pre-pregnancy BMI and neonatal adiposity.
| S-EPMC5462869 | biostudies-literature
Project description:IntroductionBMI is a tool to measure maternal nutritional status. Maternal malnutrition is frequently reported health problem especially during child bearing age and effects neonatal birth weight.AimTo determine relationship between prepregnancy maternal BMI and neonatal birth weight.Methods and materialProspective, cross sectional study conducted in Fatima Memorial Hospital, Lahore, Pakistan over a period of 1 year including 2766 mother-neonate pairs. All full term, live born neonates of both gender in early neonatal period (<72 hours) with documented maternal pre-pregnancy and/or first trimester BMI were enrolled. Data analysis using SPSS version 20, was performed.ResultsData analysis of 2766 mother-neonates pairs showed that there were 32.9% overweight and 16.5% obese mothers. More than two third of all overweight and obese mothers were of age group between 26-35 years. Diabetes mellitus, hypertension, medical illness, uterine malformations and caesarean mode of delivery were more prevalent in obese mothers as 22.8%, 10.1%, 13.2%, 2.6% and 75.4% respectively. Mean birth weight, length and OFC increased with increasing maternal BMI. Comparing for normal weight mothers, underweight mothers were at increased risk of low birth weight (p< 0.01) and low risk of macrosomic neonates (p<0.01). However overweight and obese mothers were comparable to normal weight mothers for delivering macrosomic neonates (p 0.89 and p 0.66 respectively).ConclusionsOur study highlights that direct relationship exists between maternal BMI and neonatal birth weight.
| S-EPMC7592734 | biostudies-literature
Project description:AimsA growing body of evidence suggests that a higher maternal pre-pregnancy body mass index results in higher offspring's blood pressure, but there is inconsistency about the impact of father's body mass index. Furthermore, evidence is limited with regard to low and middle income countries. We aimed to determine the association between parental pre-pregnancy body mass index and offspring's blood pressure during the first year of life.MethodsIn 587 infants of the BReastfeeding Attitude and Volume Optimization (BRAVO) trial systolic and diastolic blood pressure were measured twice at the right leg in a supine position, using an automatic oscillometric device at day 7, month 1, 2, 4, 6, 9 and 12. Parental pre-pregnancy body mass index was based on self-reported weight and height. Linear mixed models were performed to investigate the associations between parental pre-pregnancy body mass index and offspring blood pressure patterns.ResultsEach unit increase in maternal body mass index was associated with 0.24 mmHg (95% confidence interval 0.05; 0.44) and 0.13 mmHg (0.01; 0.25) higher offspring's mean systolic and diastolic blood pressure, respectively, during the first year of life. A higher offspring blood pressure with increased maternal pre-pregnancy body mass index was seen at birth and remained higher during the first year of life. The association with systolic blood pressure remained similar after including birth size and offspring's weight and height over time. The association with diastolic blood pressure attenuated slightly to a non-significant result after including these variables. Paternal body mass index was not associated with offspring's blood pressure.ConclusionHigher maternal pre-pregnancy body mass index, but not paternal pre-pregnancy body mass index, is associated with higher offspring blood pressure already from birth onwards.
| S-EPMC6753651 | biostudies-literature