Sex and fetal genome influence gene expression in pig endometrium at the end of gestation.

BACKGROUND: A fine balance of feto-maternal resource allocation is required to support pregnancy, which depends on interactions between maternal and fetal genetic potential, maternal nutrition and environment, endometrial and placental functions. In particular, some imprinted genes have a role in regulating maternal-fetal nutrient exchange, but few have been documented in the endometrium. The aim of this study is to describe the expression of 42 genes, with parental expression, in the endometrium comparing two extreme breeds: Large White (LW); Meishan (MS) with contrasting neonatal mortality and maturity at two days of gestation (D90-D110). We investigated their potential contribution to fetal maturation exploring genes-fetal phenotypes relationships. Last, we hypothesized that the fetal genome and sex influence their endometrial expression. For this purpose, pure and reciprocally crossbred fetuses were produced using LW and MS breeds. Thus, in the same uterus, endometrial samples were associated with its purebred or crossbred fetuses. RESULTS: Among the 22 differentially expressed genes (DEGs), 14 DEGs were differentially regulated between the two days of gestation. More gestational changes were described in LW (11 DEGs) than in MS (2 DEGs). Nine DEGs were differentially regulated between the two extreme breeds, highlighting differences in the regulation of endometrial angiogenesis, nutrient transport and energy metabolism. We identified DEGs that showed high correlations with indicators of fetal maturation, such as ponderal index at D90 and fetal blood fructose level and placental weight at D110. We pointed out for the first time the influence of fetal sex and genome on endometrial expression at D90, highlighting AMPD3, CITED1 and H19 genes. We demonstrated that fetal sex affects the expression of five imprinted genes in LW endometrium. Fetal genome influenced the expression of four genes in LW endometrium but not in MS endometrium. Interestingly, both fetal sex and fetal genome interact to influence endometrial gene expression. CONCLUSIONS: These data provide evidence for some sexual dimorphism in the pregnant endometrium and for the contribution of the fetal genome to feto-maternal interactions at the end of gestation. They suggest that the paternal genome may contribute significantly to piglet survival, especially in crossbreeding production systems.

Intrauterine growth and the tangential expansion of the human cerebral cortex in times of food scarcity and abundance.

Tangential growth of the human cerebral cortex is driven by cell proliferation during the first and second trimester of pregnancy. Fetal growth peaks in mid-gestation. Here, we explore how genes associated with fetal growth relate to cortical growth. We find that both maternal and fetal genetic variants associated with higher birthweight predict larger cortical surface area. The relative dominance of the maternal vs. fetal variants in these associations show striking variations across birth years (1943 to 1966). The birth-year patterns vary as a function of the epigenetic status near genes differentially methylated in individuals exposed (or not) to famine during the Dutch Winter of 1944/1945. Thus, it appears that the two sets of molecular processes contribute to early cortical development to a different degree in times of food scarcity or its abundance.

The influence of insulin-related genetic variants on fetal growth, fetal blood flow, and placental weight in a prospective pregnancy cohort.

The fetal insulin hypothesis proposes that low birthweight and type 2 diabetes (T2D) in adulthood may be two phenotypes of the same genotype. In this study we aimed to explore this theory further by testing the effects of GWAS-identified genetic variants related to insulin release and sensitivity on fetal growth and blood flow from week 20 of gestation to birth and on placental weight at birth. We calculated genetic risk scores (GRS) of first phase insulin release (FPIR), fasting insulin (FI), combined insulin resistance and dyslipidaemia (IR + DLD) and insulin sensitivity (IS) in a study population of 665 genotyped newborns. Two-dimensional ultrasound measurements with estimation of fetal weight and blood flow were carried out at week 20, 25, and 32 of gestation in all 665 pregnancies. Birthweight and placental weight were registered at birth. Associations between the GRSs and fetal growth, blood flow and placental weight were investigated using linear mixed models. The FPIR GRS was directly associated with fetal growth from week 20 to birth, and both the FI GRS, IR + DLD GRS, and IS GRS were associated with placental weight at birth. Our findings indicate that insulin-related genetic variants might primarily affect fetal growth via the placenta.

Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.

Maternal blood transcriptome as a sensor of fetal organ maturation at the end of organogenesis in cattle†.

Harnessing information from the maternal blood to predict fetal growth is attractive yet scarcely explored in livestock. The objectives were to determine the transcriptomic modifications in maternal blood and fetal liver, gonads, and heart according to fetal weight and to model a molecular signature based on the fetal organs allowing the prediction of fetal weight from the maternal blood transcriptome in cattle. In addition to a contemporaneous maternal blood sample, organ samples were collected from 10 male fetuses at 42 days of gestation for RNA-sequencing. Fetal weight ranged from 1.25 to 1.69 g (mean = 1.44 ± 0.15 g). Clustering data analysis revealed clusters of co-expressed genes positively correlated with fetal weight and enriching ontological terms biologically relevant for the organ. For the heart, the 1346 co-expressed genes were involved in energy generation and protein synthesis. For the gonads, the 1042 co-expressed genes enriched seminiferous tubule development. The 459 co-expressed genes identified in the liver were associated with lipid synthesis and metabolism. Finally, the cluster of 571 co-expressed genes determined in maternal blood enriched oxidative phosphorylation and thermogenesis. Next, data from the fetal organs were used to train a regression model of fetal weight, which was predicted with the maternal blood data. The best prediction was achieved when the model was trained with 35 co-expressed genes overlapping between heart and maternal blood (root-mean-square error = 0.04, R2 = 0.93). In conclusion, linking transcriptomic information from maternal blood with that from the fetal heart unveiled maternal blood as a predictor of fetal development.

Feto-maternal cholesterol transport regulated by ß-Klotho-FGF15 axis is essential for fetal growth.

ß-Klotho (ß-KL) is indispensable to regulate lipid, glucose, and energy metabolism in adult animals. ß-KL is highly expressed in the yolk sac, but its role in the developmental stages has not been established. We hypothesized that ß-KL is required for metabolic regulation in the embryo and aimed to clarify the role of ß-KL during development. Here, we show that ß-KL regulates feto-maternal cholesterol transport through the yolk sac by mediating FGF 15 signaling, and also that impairment of the ß-KL-FGF15 axis causes fetal growth restriction (FGR). Embryos of ß- kl knockout (ß-kl-/-) mice were morphologically normal but exhibited FGR before placental maturation. The body weight of ß-kl-/- mice remained lower after birth. ß-KL deletion reduced cholesterol supply from the maternal blood and led to lipid shortage in the embryos. These phenotypes were similar to those of embryos lacking FGF15, indicating that ß-KL-FGF15 axis is essential for growth and lipid regulation in the embryonic stages. Our findings suggest that lipid abnormalities in early gestation provoke FGR, leading to reduced body size in later life.

Effect of birth rank, and placentome subtype on expression of genes involved in placental nutrient transport in sheep.

Placental function is a key determinant of fetal growth and development that can be influenced by maternal and fetal environmental factors. The molecular mechanisms by which the placenta senses and responds to environmental cues are poorly understood. This exploratory study aimed to characterize the effect of birth rank (single vs. twin) and placentome morphologic subtype on expression of genes involved in nutrient transport, angiogenesis, immunity and stress response. Cotyledonary tissue was collected from type A, B and C placentomes from five single and six twin fetuses at 140 days of gestation. GLUT1 and GLUT3 were the most highly expressed genes consistent with the high demand for glucose to support fetal growth. Expression of BCKDHß and IGF-2 was 1.3- and 1.5-fold higher, respectively, and PCYT1A was 3-fold lower in singles compared to twins (P < 0.05) while no other differences in gene expression were observed between birth ranks. Expression of EAAT2 and LAT2 was higher while PCYT1A was lower in A compared to B type cotyledons. Expression of GUCY1B1/3 and IGF-1 was higher while CD98 and LAT2 were lower in type B compared to C cotyledons (P < 0.05). Compared to type C cotyledons, expression of EAAT2, IGF-1, IGF-2, LAT1 was higher, while TEK was lower in type A cotyledons. The effects of birth rank on placental gene expression in this study indicated that placental nutrient transport and/or function differs between single and twin pregnancies in sheep. Differences in gene expression between the placentome subtypes suggests that changes in placentome morphology are associated with shifts in amino acid transport and metabolism, oxidative stress and angiogenesis and/or blood flow. This study highlights that placental gene expression differs in response to birth rank and placentome morphologic subtype which suggests that both maternal and fetal factors may influence placental function in sheep. These associations provide insights into gene pathways for more targeted future investigations as well as potential adaptations to improve placental efficiency to support fetal growth in twin pregnancies.

Integrated Placental Modelling of Histology with Gene Expression to Identify Functional Impact on Fetal Growth.

Fetal growth restriction (FGR) is a leading cause of perinatal morbidity and mortality. Altered placental formation and functional capacity are major contributors to FGR pathogenesis. Relating placental structure to function across the placenta in healthy and FGR pregnancies remains largely unexplored but could improve understanding of placental diseases. We investigated integration of these parameters spatially in the term human placenta using predictive modelling. Systematic sampling was able to overcome heterogeneity in placental morphological and molecular features. Defects in villous development, elevated fibrosis, and reduced expression of growth and functional marker genes (IGF2, VEGA, SLC38A1, and SLC2A3) were seen in age-matched term FGR versus healthy control placentas. Characteristic histopathological changes with specific accompanying molecular signatures could be integrated through computational modelling to predict if the placenta came from a healthy or FGR pregnancy. Our findings yield new insights into the spatial relationship between placental structure and function and the etiology of FGR.

Moderate maternal nutrient reduction in pregnancy alters fatty acid oxidation and RNA splicing in the nonhuman primate fetal liver.

Fetal liver tissue collected from a nonhuman primate (NHP) baboon model of maternal nutrient reduction (MNR) at four gestational time points (90, 120, 140, and 165 days gestation [dG], term in the baboon is ∼185 dG) was used to quantify MNR effects on the fetal liver transcriptome. 28 transcripts demonstrated different expression patterns between MNR and control livers during the second half of gestation, a developmental period when the fetus undergoes rapid weight gain and fat accumulation. Differentially expressed transcripts were enriched for fatty acid oxidation and RNA splicing-related pathways. Increased RNA splicing activity in MNR was reflected in greater abundances of transcript splice variant isoforms in the MNR group. It can be hypothesized that the increase in splice variants is deployed in an effort to adapt to the poor in utero environment and ensure near-normal development and energy metabolism. This study is the first to study developmental programming across four critical gestational stages during primate fetal liver development and reveals a potentially novel cellular response mechanism mediating fetal programming in response to MNR.

Placental nanoparticle gene therapy normalizes gene expression changes in the fetal liver associated with fetal growth restriction in a fetal sex-specific manner.

Fetal growth restriction (FGR) is associated with increased risk of developing non-communicable diseases. We have a placenta-specific nanoparticle gene therapy protocol that increases placental expression of human insulin-like growth factor 1 (hIGF1), for the treatment of FGR in utero. We aimed to characterize the effects of FGR on hepatic gluconeogenesis pathways during early stages of FGR establishment, and determine whether placental nanoparticle-mediated hIGF1 therapy treatment could resolve differences in the FGR fetus. Female Hartley guinea pigs (dams) were fed either a Control or Maternal Nutrient Restriction (MNR) diet using established protocols. At GD30-33, dams underwent ultrasound guided, transcutaneous, intraplacental injection of hIGF1 nanoparticle or PBS (sham) and were sacrificed 5 days post-injection. Fetal liver tissue was fixed and snap frozen for morphology and gene expression analysis. In female and male fetuses, liver weight as a percentage of body weight was reduced by MNR, and not changed with hIGF1 nanoparticle treatment. In female fetal livers, expression of hypoxia inducible factor 1 (Hif1α) and tumor necrosis factor (Tnfα) were increased in MNR compared to Control, but reduced in MNR + hIGF1 compared to MNR. In male fetal liver, MNR increased expression of Igf1 and decreased expression of Igf2 compared to Control. Igf1 and Igf2 expression was restored to Control levels in the MNR + hIGF1 group. This data provides further insight into the sex-specific mechanistic adaptations seen in FGR fetuses and demonstrates that disruption to fetal developmental mechanisms may be returned to normal by treatment of the placenta.

Epigenetic modifications and fetal programming: Molecular mechanisms to control hypertension inheritance.

Cardiovascular diseases (CVD) are the number 1 cause of death in the United States and hypertension is a highly prevalent risk factor for CVD. It is estimated that up to 50 % of the hypertensive trait is genetically inherited while the other 50 % is determined by modifiable factors involving lifestyle, behaviors, and the environment. Interestingly, the hypertensive trait is induced or inhibited by epigenetic modifications modulated by modifiable factors. This review focused on the underlying mechanisms of stress, sleep deprivation, obesity and sedentarism as key players for epigenetic modifications contributing to the development of the hypertensive trait and, on the other hand, how epigenetic modifications induced by physical exercise and healthier habits may contribute to overturn and prevent the inheritance of hypertension trait. Furthermore, adversities during gestation and perinatal life also increase the risk for hypertension and CVD later in life, which can perpetuate the inheritance of the hypertensive trait whereas healthier habits during gestation and lactation may counteract fetal programming to improve the cardiovascular health of the progeny. Therefore, it is promising that a healthier lifestyle causes long-lasting epigenetic modifications and is transmitted to the next generation, strengthening the fight against the inheritance of hypertension.

Copy number variants and fetal growth in stillbirths.

BACKGROUND: Fetal growth abnormalities are associated with a higher incidence of stillbirth, with small and large for gestational age infants incurring a 3 to 4- and 2 to 3-fold increased risk, respectively. Although clinical risk factors such as diabetes, hypertension, and placental insufficiency have been associated with fetal growth aberrations and stillbirth, the role of underlying genetic etiologies remains uncertain. OBJECTIVE: This study aimed to assess the relationship between abnormal copy number variants and fetal growth abnormalities in stillbirths using chromosomal microarray. STUDY DESIGN: A secondary analysis utilizing a cohort study design of stillbirths from the Stillbirth Collaborative Research Network was performed. Exposure was defined as abnormal copy number variants including aneuploidies, pathogenic copy number variants, and variants of unknown clinical significance. The outcomes were small for gestational age and large for gestational age stillbirths, defined as a birthweight <10th percentile and greater than the 90th percentile for gestational age, respectively. RESULTS: Among 393 stillbirths with chromosomal microarray and birthweight data, 16% had abnormal copy number variants. The small for gestational age outcome was more common among those with abnormal copy number variants than those with a normal microarray (29.5% vs 16.5%; P=.038). This finding was consistent after adjusting for clinically important variables. In the final model, only abnormal copy number variants and maternal age remained significantly associated with small for gestational age stillbirths, with an adjusted odds ratio of 2.22 (95% confidence interval, 1.12-4.18). Although large for gestational age stillbirths were more likely to have an abnormal microarray: 6.2% vs 3.3% (P=.275), with an odds ratio of 2.35 (95% confidence interval, 0.70-7.90), this finding did not reach statistical significance. CONCLUSION: Genetic abnormalities are more common in the setting of small for gestational age stillborn fetuses. Abnormal copy number variants not detectable by traditional karyotype make up approximately 50% of the genetic abnormalities in this population.

Genome-wide placental DNA methylations in fetal overgrowth and associations with leptin, adiponectin and fetal growth factors.

BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.

Serum adiponectin levels and adiponectin +276 G/T gene polymorphism in newborns with large and small birth weights.

PURPOSE: Adiponectin may be an important indicator in the regulation of fetal and neonatal growth due to its metabolism, energy balance, and insulin-sensitizing action. The current study's goal was to determine if there is a link between adiponectin +276 G/T gene polymorphism and serum adiponectin level in newborns classified as appropriate for gestational age (AGA), small for gestational age (SGA), or large for gestational age (LGA). METHODS: The study included newborns classified as AGA (n = 65), SGA (n = 65), or LGA (n = 65) according to their gestational age or birth weight. To determine the presence of adiponectin +276 G/T gene polymorphism, genotyping was done using polymerase chain reaction-restriction fragment length polymorphism. Enzyme-linked immunosorbent assay was used to determine the level of adiponectin in the blood. RESULTS: The SGA newborns had significantly lower levels of serum adiponectin than the AGA and LGA newborns. There were statistically significant differences between the genotype frequencies (GG, GT, TT) of the SGA newborns (29.9%, 45.1%, 13.9%), the AGA newborns (41.6%, 20.7%, 44.4%), and the LGA newborns (28.6%, 34.1%, 41.7%) (chi-square = 15.8; degree of freedom = 4; p = .003). The newborns carrying the GT genotype had an increased risk of being SGA compared to those carrying the GG and TT genotypes (odds ratio [OR] = 3.07; confidence interval [CI] = 95% (1.38-6.64); p = .005 and OR = 6.96; CI = 95% (2.19-22.1); p < .001, respectively). The newborns carrying the GG and TT genotypes had better protection against being SGA than those carrying the GT genotype (OR = 0.33; CI = 95% (0.15-0.72); p = .005 and OR = 0.14; CI = 95% (0.05-0.46); p < .001, respectively). The newborns carrying the GT genotype had lower birth weights, head circumferences, and ponderal indices than those carrying the TT genotype (p < .001). The serum adiponectin levels between adiponectin +276 G/T genotypes did not differ significantly (p = .429). In addition, serum adiponectin level showed a significant positive correlation with birth weight, birth length, head circumference, and ponderal index in all newborns. CONCLUSION: The results of the current study suggest that the adiponectin +276 G/T gene polymorphism was associated with an increased chance of being born SGA or LGA. The effect of this polymorphism on newborn birth size was independently associated with serum adiponectin levels. Adiponectin may play a role in fetal growth.

Mycotoxin ingestion during late gestation alters placentome structure, cotyledon transcriptome, and fetal development in pregnant sheep.

Ergot alkaloids, a class of mycotoxins, induce vasoconstriction when consumed by animals and humans. Pregnant ewes (n = 16; 81.2 kg ± 7.7) were assigned fed endophyte-infected tall fescue seed (E+; 4.14 µg ergovaline + ergovalinine/g seed) or a control diet (CON; 0 µg ergovaline + ergovalinine) for increasing duration during late gestation (from gd86 to gd110 or gd133) to examine changes in placentome morphology and mRNA transcriptome, and fetal development. Exposure to E+ fescue reduced serum prolactin concentrations at gd110 and gd133 demonstrating treatment efficacy. For control ewes, cotyledon and total placentome weights decreased with advancing gestation due to remodeling of placental tissues; however, cotyledon and placentome weight did not change with advancing gestation in E+ fed ewes. Fetal brain sparing was evident in E+ exposed fetuses at gd110 and gd133 compared to CON, which demonstrates asymmetrical growth and intrauterine growth restriction. Mycotoxin exposure (E+) resulted in differential expression of 22 genes in the cotyledon tissue at gd110 but only one gene at gd133 compared to CON. These results suggest that the response to mycotoxin exposure in the pregnant sheep model has an immediate impact on placental remodeling and fetal development that persists throughout the duration of the exposure period.

Gestational Nutrition as a Predisposing Factor to Obesity Onset in Offspring: Role for Involvement of Epigenetic Mechanism.

Maternal lifestyle has been implicated as a predisposing factor in the development of metabolic disorders in adulthood. This lifestyle includes the immediate environment, physical activity and nutrition. Maternal nutrition has direct influence on the developmental programming through biochemical alterations and can lead to modifications in the fetal genome through epigenetic mechanisms. Imbalance in basic micro or macro nutrients due to famine or food deficiency during delicate gestational periods can lead to onset of metabolic syndrome including obesity. A major example is the Dutch famine which led to a serious metabolic disorder in adulthood of affected infants. Notably due to gene variants, individualized responses to nutritional deficiencies are unconventional, therefore intensifying the need to study nutritional genomics during fetal programming. Epigenetic mechanisms can cause hereditary changes without changing the DNA sequence; the major mechanisms include small non-coding RNAs, histone modifications and most stable of all is DNA methylation. The significance association between obesity and DNA methylation is through regulation of genes implicated in lipid and glucose metabolism either directly or indirectly by hypomethylation or hypermethylation. Examples include CPT1A, APOA2, ADRB3 and POMC. Any maternal exposure to malnutrition or overnutrition that can affect genes regulating major metabolic pathways in the fetus, will eventually cause underlying changes that can predispose or cause the onset of metabolic disorder in adulthood. In this review, we examined the interaction between nutrition during gestation and epigenetic programming of metabolic syndrome.

Identification of eQTLs and differential gene expression associated with fetal programming in beef cattle.

This study assessed differential gene expression and identified expression quantitative trait loci (eQTLs) from samples of Longissimus lumborum muscle from bulls at 15 months of age submitted to different prenatal nutrition. Upon confirmation of pregnancy, 126 dams were separated into three diet treatments varying the period of inclusion of energy protein supplementation (NP, PP, and FP). At calving, 63 males were genotyped with GGP LD BeadChip. The skeletal muscle of 15 bulls was sequenced (RNA-seq) at 15 months of age. The EdgeR package was used for differential gene expression and principal component analysis (PCA), and the Matrix eQTL package was used for the eQTLs analysis (R statistical). The functional enrichment analysis was performed using the MetaCore® software. No genes differentially expressed were found between treatments (FDR > 0.05); nevertheless, we found 179 cis-tag-eQTLs and 20,762 trans-tag-eQTLs (FDR < 0.05) after linkage disequilibrium analysis. The functional enrichment analysis identified terms from gene ontology related to genes associated to trans-eQTLs (FDR < 0.05) as well as metabolic pathways (> gScore). Most biological pathways and genes found had been previously associated to fetal programming. The different prenatal supplementation strategies did not impact on muscle transcriptome of bulls. Additionally, there is a link between genotype and gene expression levels related to developmental traits in Nellore cattle.

Fetal origin of sex-bias brain aging.

DNA methylation plays crucial roles during fetal development as well as aging. Whether the aging of the brain is programmed at the fetal stage remains untested. To test this hypothesis, mouse epigenetic clock (epiclock) was profiled in fetal (gestation day 15), postnatal (day 5), and aging (week 70) brain of male and female C57BL/6J inbred mice. Data analysis showed that on week 70, the female brain was epigenetically younger than the male brain. Predictive modeling by neural network identified specific methylations in the brain at the developing stages that were predictive of epigenetic state of the brain during aging. Transcriptomic analysis showed coordinated changes in the expression of epiclock genes in the fetal brain relative to the placenta. Whole-genome bisulfite sequencing identified sites that were methylated both in the placenta and fetal brain in a sex-specific manner. Epiclock genes and genes associated with specific signaling pathways, primarily the gonadotropin-releasing hormone receptor (GnRHR) pathway, were associated with the sex-bias methylations in the placenta as well as the fetal brain. Transcriptional crosstalk among the epiclock and GnRHR pathway genes was evident in the placenta that was maintained in the brain during development as well as aging. Collectively, these findings suggest that sex differences in the aging of the brain are of fetal origin and epigenetically linked to the placenta.