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Sex differences in the associations of placental epigenetic aging with fetal growth.

ABSTRACT: Identifying factors that influence fetal growth in a sex-specific manner can help unravel mechanisms that explain sex differences in adverse neonatal outcomes and in-utero origins of cardiovascular disease disparities. Premature aging of the placenta, a tissue that supports fetal growth and exhibits sex-specific epigenetic changes, is associated with pregnancy complications. Using DNA methylation-based age estimator, we investigated the sex-specific relationship of placental epigenetic aging with fetal growth across 13-40 weeks gestation, neonatal size, and risk of low birth weight. Placental epigenetic age acceleration (PAA), the difference between DNA methylation age and gestational age, was associated with reduced fetal weight among males but with increased fetal weight among females. PAA was inversely associated with fetal weight, abdominal circumference, and biparietal diameter at 32-40 weeks among males but was positively associated with all growth measures among females across 13-40 weeks. A 1-week increase in PAA was associated with 2-fold (95% CI 1.2, 3.2) increased odds for low birth weight and 1.5-fold (95% CI 1.1, 2.0) increased odds for small-for-gestational age among males. In all, fetal growth was significantly reduced in males but not females exposed to a rapidly aging placenta. Epigenetic aging of the placenta may underlie sex differences in neonatal outcomes.

SUBMITTER: Tekola-Ayele F

PROVIDER: S-EPMC6710059 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Sex differences in the associations of placental epigenetic aging with fetal growth.

Tekola-Ayele Fasil F Workalemahu Tsegaselassie T Gorfu Gezahegn G Shrestha Deepika D Tycko Benjamin B Wapner Ronald R Zhang Cuilin C Louis Germaine M Buck GMB

Aging 20190808 15

Identifying factors that influence fetal growth in a sex-specific manner can help unravel mechanisms that explain sex differences in adverse neonatal outcomes and <i>in-utero</i> origins of cardiovascular disease disparities. Premature aging of the placenta, a tissue that supports fetal growth and exhibits sex-specific epigenetic changes, is associated with pregnancy complications. Using DNA methylation-based age estimator, we investigated the sex-specific relationship of placental epigenetic ag ...[more]

PMID: 31395791

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Project description:Fetal overgrowth "programs" an elevated risk of type 2 diabetes in adulthood. Epigenetic alterations may be a mechanism in programming the vulnerability. We sought to characterize genome-wide alterations in placental gene methylations in fetal overgrowth and the associations with metabolic health biomarkers including leptin, adiponectin and fetal growth factors. Comparing genome-wide placental gene DNA methylations in large-for-gestational-age (LGA, an indicator of fetal overgrowth, n = 30) versus optimal-for-gestational-age (OGA, control, n = 30) infants using the Illumina Infinium Human Methylation-EPIC BeadChip, we identified 543 differential methylation positions (DMPs; 397 hypermethylated, 146 hypomethylated) at false discovery rate < 5% and absolute methylation difference > 0.05 after adjusting for placental cell-type heterogeneity, maternal age, pre-pregnancy BMI and HbA1c levels during pregnancy. Twenty-five DMPs annotated to 20 genes (QSOX1, FCHSD2, LOC101928162, ADGRB3, GCNT1, TAP1, MYO16, NAV1, ATP8A2, LBXCOR1, EN2, INCA1, CAMTA2, SORCS2, SLC4A4, RPA3, UMAD1,USP53, OR2L13 and NR3C2) could explain 80% of the birth weight variations. Pathway analyses did not detect any statistically significant pathways after correcting for multiple tests. We validated a newly discovered differentially (hyper-)methylated gene-visual system homeobox 1 (VSX1) in an independent pyrosequencing study sample (LGA 47, OGA 47). Our data confirmed a hypermethylated gene-cadherin 13 (CDH13) reported in a previous epigenome-wide association study. Adiponectin in cord blood was correlated with its gene methylation in the placenta, while leptin and fetal growth factors (insulin, IGF-1, IGF-2) were not. Fetal overgrowth may be associated with a large number of altered placental gene methylations. Placental VSX1 and CDH13 genes are hypermethylated in fetal overgrowth. Placental ADIPOQ gene methylations and fetal circulating adiponectin levels were correlated, suggesting the contribution of placenta-originated adiponectin to cord blood adiponectin.

Project description:BackgroundWorldwide, stillbirth is one of the leading causes of death. Altered fetal growth and placental abnormalities are the strongest and most prevalent known risk factors for stillbirth. The aim of this study was to identify patterns of association between placental abnormalities, fetal growth, and stillbirth.Methods and findingsPopulation-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in 5 geographic areas in the U.S. Fetal growth abnormalities were categorized as small (<10th percentile) and large (>90th percentile) for gestational age at death (stillbirth) or delivery (live birth) using a published algorithm. Placental examination by perinatal pathologists was performed using a standardized protocol. Data were weighted to account for the sampling design. Among 319 singleton stillbirths and 1119 singleton live births at ?24 weeks at death or delivery respectively, 25 placental findings were investigated. Fifteen findings were significantly associated with stillbirth. Ten of the 15 were also associated with fetal growth abnormalities (single umbilical artery; velamentous insertion; terminal villous immaturity; retroplacental hematoma; parenchymal infarction; intraparenchymal thrombus; avascular villi; placental edema; placental weight; ratio birth weight/placental weight) while 5 of the 15 associated with stillbirth were not associated with fetal growth abnormalities (acute chorioamnionitis of placental membranes; acute chorioamionitis of chorionic plate; chorionic plate vascular degenerative changes; perivillous, intervillous fibrin, fibrinoid deposition; fetal vascular thrombi in the chorionic plate). Five patterns were observed: placental findings associated with (1) stillbirth but not fetal growth abnormalities; (2) fetal growth abnormalities in stillbirths only; (3) fetal growth abnormalities in live births only; (4) fetal growth abnormalities in stillbirths and live births in a similar manner; (5) a different pattern of fetal growth abnormalities in stillbirths and live births.ConclusionsThe patterns of association between placental abnormalities, fetal growth, and stillbirth provide insights into the mechanism of impaired placental function and stillbirth. They also suggest implications for clinical care, especially for placental findings amenable to prenatal diagnosis using ultrasound that may be associated with term stillbirths.

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Sex differences in the associations of placental epigenetic aging with fetal growth.

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Sex differences in the associations of placental epigenetic aging with fetal growth.

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