Project description:Placental development is modified in response to maternal nutrient restriction (NR) resulting in a spectrum of fetal growth rates. Pregnant sheep carrying singleton fetuses and fed either 100% (n=8) or 50% (NR; n=28) of their National Research Council (NRC) recommended intake from Days 35 to 135 of pregnancy were used to elucidate placentome transcriptome alterations at both Day 70 and 135. NR fetuses were further designated into upper (NR NonSGA; n=7) and lower quartiles (NR SGA; n=7) based on Day 135 fetal weight. At Day 70 of pregnancy, there were 22 genes dysregulated between NR SGA and 100% NRC placentomes, 27 genes between NR NonSGA and 100% NRC placentomes, and 22 genes between NR SGA and NR NonSGA placentomes. These genes mediated molecular functions such as MHC class II protein binding, signaling receptor binding, and cytokine activity. Gene Set Enrichment Analysis (GSEA) revealed significant overrepresentation of genes for natural killer cell-mediated cytotoxicity in NR SGA compared to 100% NRC placentomes and alterations in nutrient utilization pathways between NR SGA and NR NonSGA placentomes at Day 70. Results identify novel factors associated with impaired function in SGA placentomes and potential for placentomes from NR NonSGA pregnancies to adapt to nutritional hardship.
Project description:Placental development is modified in response to maternal nutrient restriction (NR), resulting in a spectrum of fetal growth rates. Pregnant sheep carrying singleton fetuses and fed either 100% (n = 8) or 50% (NR; n = 28) of their National Research Council (NRC) recommended intake from days 35-135 of pregnancy were used to elucidate placentome transcriptome alterations at both day 70 and day 135. NR fetuses were further designated into upper (NR NonSGA; n = 7) and lower quartiles (NR SGA; n = 7) based on day 135 fetal weight. At day 70 of pregnancy, there were 22 genes dysregulated between NR SGA and 100% NRC placentomes, 27 genes between NR NonSGA and 100% NRC placentomes, and 22 genes between NR SGA and NR NonSGA placentomes. These genes mediated molecular functions such as MHC class II protein binding, signaling receptor binding, and cytokine activity. Gene set enrichment analysis (GSEA) revealed significant overrepresentation of genes for natural-killer-cell-mediated cytotoxicity in NR SGA compared to 100% NRC placentomes, and alterations in nutrient utilization pathways between NR SGA and NR NonSGA placentomes at day 70. Results identify novel factors associated with impaired function in SGA placentomes and potential for placentomes from NR NonSGA pregnancies to adapt to nutritional hardship.
Project description:The aim of this study was to identify fetal adaptations to gene expression in our mouse model of intrauterine growth restriction (IUGR). Starting at E6.5, pregnant CD-1 mice received either control (ad libitum) or 70% of ad libitum food (maternal nutrient restriction [MNR]). At E18.5, fetal right liver lobes were collected from 2 pups/litter in litters with 11-15 pups. Frozen liver was homogenized for RNA isolations. Isolated RNA was sequenced on a HiSeq2500 with an average read depth of 23M reads and a range of 17-31M reads per sample. Reads were aligned to the mm9 transcriptome with Bowtie2. Normalization and differential expression was done with DESeq2, ALDex2 and EdgeR, and genes were considered in the study if they were consistent in 2 or more tools (FDR <0.1).
Project description:Concentrations of leptin decline during food restriction. This study was designed to test the hypothesis that some of the effects of maternal food restriction on placental development are mediated by the loss of leptin. Mice were randomized to 3 treatment groups on day 1.5 of pregnancy: (1) ad libitum fed (control) (2) 50% food restriction (restricted) (3) 50% food restriction with leptin replacement (1µg/g body weight/day) (leptin). On day 11.5 placentas were collected, and two placentas from each mother were pooled for microarray analysis.
Project description:Concentrations of leptin decline during food restriction. This study was designed to test the hypothesis that some of the effects of maternal food restriction on placental development are mediated by the loss of leptin.
Project description:Maternal nutrient restriction impairs placental growth and development, but available evidence suggests that adaptive mechanisms exist, in a subset of nutrient restricted (NR) ewes, that support normal fetal growth and do not result in intrauterine growth restriction (IUGR). This study utilized Affymetrix GeneChip Bovine and Ovine Genome 1.0 ST Arrays to identify novel placental genes associated with differential fetal growth rates within NR ewes. Singleton pregnancies were generated by embryo transfer and, beginning on Day 35 of pregnancy, ewes received either a 100% National Research Council (NRC) (control-fed group; n = 7) or 50% NRC (NR group; n = 24) diet until necropsy on Day 125. Fetuses from NR ewes were separated into NR non-IUGR (n = 6) and NR IUGR (n = 6) groups based on Day 125 fetal weight for microarray analysis. Of the 103 differentially expressed genes identified, 15 were upregulated and 88 were downregulated in NR non-IUGR compared to IUGR placentomes. Bioinformatics analysis revealed that upregulated gene clusters in NR non-IUGR placentomes associated with cell membranes, receptors, and signaling. Downregulated gene clusters associated with immune response, nutrient transport, and metabolism. Results illustrate that placentomal gene expression in late gestation is indicative of an altered placental immune response, which is associated with enhanced fetal growth, in a subpopulation of NR ewes.
Project description:Fetal growth restriction (FGR) develops when fetal nutrient availability is compromised and increases the risk for perinatal complications and predisposes for offspring obesity, diabetes and cardiovascular disease later in life. Emerging evidence implicates changes in placental function in altered fetal growth and the subsequent development of adult disease. The susceptibility for disease in response to an adverse intrauterine environment differs distinctly between boys and girls, with girls typically having better outcomes. Here, we test the hypothesis that regulation of the placental transcriptome by moderate nutrient reduction is dependent on fetal sex. We used a non-human primate model of FGR in which maternal global food intake is reduced by 30% starting at gestational day (GD) 30. At GD 165 (term = GD 183) placental genome expression profiling was carried out followed by bioinformatics including pathway and network analysis. Surprisingly, there was no coordinated placental molecular response to decreased nutrient availability when analyzing the data without accounting for fetal sex. In contrast, female placentas exhibited a highly coordinated response that included up-regulation of genes in networks, pathways and functional groups related to programmed cell death and down-regulation of genes in networks, pathways and functional groups associated with cell proliferation. These changes were not apparent in the male placentas. Our data support the concept that female placentas initiate complex adaptive responses to an adverse intrauterine environment, which may contribute to increased survival and better pregnancy outcomes in girls. Total RNA obtained from 165dGA control female (n=3), control male (n=3), nutrient restricted female (n=3), and nutrient restricted male (n=3) pregnancies.
Project description:Fetal growth restriction (FGR) affects between 5-10% of all live births. Placental insufficiency is a leading cause of FGR, resulting in reduced nutrient and oxygen delivery to the fetus. Currently, there is no effective in utero treatment options for FGR, or placental insufficiency. We have developed a gene therapy to deliver human insulin-like 1 growth factor (hIGF1) to the placenta via a non-viral nanoparticle delivery mechanism as potential treatment of FGR. Using a guinea pig maternal nutrient restriction (MNR) model of FGR, we aimed to understand the transcriptional changes within the placenta associated with placental insufficiency that occur at the beginning stages of FGR (mid-pregnancy), and the immediate impact of hIGF1 nanoparticle treatment on the placental transcriptome. Using RNAsequencing, we analyzed protein coding genes of three experimental groups: Control dams and MNR receiving a sham treatment, and MNR dams receiving hIGF1 nanoparticle treatment. Pathway enrichment analysis comparing MNR placentas to Control revealed upregulation of pathways associated with degradation and repair of genetic information and downregulation of pathways associated with transmembrane transport. Similarly, differentially expressed genes that were decreased in MNR + hIGF1 placentas compared to Control demonstrated downregulation in pathways relating to transporter activities, but upregulation in pathways associated with positive regulation of phosphorylation and kinase activity. When compared to MNR placentas, MNR + hIGF1 placentas demonstrated changes to genes associated with transmembrane transporter activity including ion, vitamin and solute carrier (SLC-mediated) transport. Overall, this study identifies the key signaling and metabolic changes occurring in the placenta that contribute to placental insufficiency, and increases our understanding of the pathways that increasing placental IGF1 expression acts on and corrects.
Project description:Malnutrition in women of childbearing age is associated with an increased risk of fetal growth restriction and poor infant development. Climate change, specifically the rise in ambient temperature, is thought to exacerbate the effects of malnutrition. However, few mechanistic studies exist to examine the interactions between maternal nutrition and ambient temperature on fetal growth. Here we develop a novel animal model of marginal micronutrient insufficiency and modest heat stress during pregnancy to understand interactive effects on fetal growth in mice. Female C57BL6/J mice (8 wk old, n = 6-8/group) were given ad libitum access to either AIN-93G (CON) or a modified AIN-93 diets containing 70% mineral, micronutrient, and vitamin mix (70MMV) for 4 weeks. After breeding females were housed at either 22⁰C or 33⁰C in an environmental chamber for the duration of pregnancy while remaining on their respective diets. Mice fed 70MMV diet had significantly reduced body weight gains during pregnancy in comparison to CON diet fed group. Serum K, Fe, Zn, and Se levels showed reduced levels either by diet or temperature. A novel interaction between modest heat and micronutrient insufficiency was identified and led to an altered placenta transcriptome and fetal growth restriction in this model. Sexually dimorphic differences were observed in placental and fetal tissues in the temperature groups. In males, placenta gene expression related to vascularization, nutrient transport, and stress-related responses (i.e. ER stress and inflammation) were impacted in the combination group exposed to 70MMV diet and elevated temperature, while in females the same biological functions were affected only in the CON-33C group. Collectively, our results point to an interaction between modest heat and micronutrient insufficiency on placental dysfunction and the pathogenesis of fetal growth restriction, highlighting the emerging nexus of maternal nutrition and heat stress typically seen in resource-restrained settings.
Project description:It is hypothesized that male fetuses are more vulnerable to in utero insults than female fetuses due to different growth strategies, and that the placenta contributes to these sex differences. Using the Four Core Genotypes mouse model, we examined sex differences in the fetal and placental responses to maternal food restriction (~60% of ad libitum) beginning mid-gestation (day 11.5), including the independent roles of chromosomal and gonadal sex. Food restriction reduced fetal and placental weights, but had no effect on the number of viable conceptuses. However, the effect of food restriction did not differ between gonadal male and female conceptuses, or between XX and XY conceptuses. Sex differences in gene expression in both the labyrinth and the combined junctional zone/ decidua, as assessed by RNA sequencing, were due entirely to chromosomal sex, and not to gonadal sex. Food restriction affected the expression of 525 and 665 genes in the labyrinth and the combined junctional zone/ decidua, respectively. However, these effects of food restriction did not differ by gonadal sex or chromosomal sex when assessed for statistical interactions. In contrast, when analysing XX and XY placentas separately, we found hundreds of genes that were affected by food restriction in one sex but not the other, including hundreds of genes not found to be significant in the combined analyses. However, estimated effect sizes were generally similar for XX and XY placentas, suggesting that these sex-stratified analyses greatly exaggerated the extent of sex-dependent responses. Overall, we did not find evidence of the hypothesized sex differences in fetal growth strategy, and found that sex differences in placental gene expression were largely due to chromosomal sex.