Project description:The study objective was to determine differentially expressed mRNA transcripts in pancreatic islets from fetal sheep with placental insufficiency-induced intrauterine growth restricted.
Project description:The study objective was to determine differentially expressed mRNA transcripts in perirenal adipose tissue from fetal sheep that underwent sham or adrenal demedullation prior to fetal growth restriction to determine the role of catecholamines on gene expression following placental insufficiency-induced intrauterine growth restriction.
Project description:The study objective was to determine differentially expressed mRNA transcripts in skeletal muscle from fetal sheep and 30 day old lambs to determine persistent gene changes following placental insufficiency-induced intrauterine growth restriction.
Project description:Placental insufficiency is implicated in the intrauterine infection-associated spontaneous preterm birth. Using a mouse model of LPS-induced intrauterine inflammation that leads to preterm delivery, RNA-seq study was performed in the placenta at gestational day 17 to assess the transcriptome changes.
Project description:Intrauterine hyperglycemia has been linked to an elevated risk of diabetes in next and further generations. Existing reports about transmission effects of intrauterine hyperglycemia have included both intrauterine and postnatal metabolic exposure factors, the impact of intrauterine hyperglycemia per se has not been separately assessed. To investigate effect of intrauterine hyperglycemia exposure per se on further generations, we selected non-phenotypic F1-GDM and F2-GDM male mice to examin metabolic changes in next generation and performed a methylome on day 13.5 primordial germ cells (PGCs) of F1-GDM male fetus to explore its underlying mechanism. We found that intrauterine hyperglycemia exposure per se resulted in obesity, insulin resistance and/or glucose intolerance in F2 male mice, and no changes in F3 male mice. Methylome of day 13.5 PGCs of F1-GDM male fetus revealed differently methylation genes enriched in obesity and diabetic pathogenesis. Methylation validation of targeted gene Fyn showed consistent hypo-methylation status in F1 PGCs, F1 fetal testis, sperm of F1/N-GDM mice, and somatic cells of F2-GDM male mice. While fetal testis of F2-GDM mice showed no alteration in Fyn methylation. Our data indicates that intrauterine hyperglycemia exposure per se contributes to metabolic changes in F2 but not F3 generation, by altering methylation erasure in PGCs of F1 generation.
Project description:Impaired muscle growth as a result of IUGR is a major contributor to lifelong reductions in muscle mass (sarcopenia) and metabolic disease risk. We use an ovine model of chronic placental insufficiency which restricts nutrient supply from mother to fetus and results in intrauterine growth restriction. In our model of placental insufficiency and IUGR, fetal hindlimb muscles weigh less than normally-grown control fetuses and have smaller myofiber diameters. Given the frequent correlation between functional changes and transcriptional changes, we investigated the effect of chronic placental insufficiency and IUGR on fetal skeletal muscle gene expression. We found that gene expression in the skeletal muscle is significantly altered by chronic placental insufficiency. In gene ontology analysis, we found that genes involved in cell cycle regulation were most significantly affected, with downregulation of several cyclins. These observations may in part account for decreased muscle weight relative to brain weight observed in the late gestation IUGR fetus.
Project description:Intrauterine growth restriction (IUGR) impairs fetal growth and development, perturbs nutrient metabolism, and increases the risk of developing diseases in the postnatal life. However, the underlying mechanisms by which IUGR affects fetuses remain incompletely understood. Here, we applied high-throughput proteomics approach and biochemical analysis to investigate the impact of IUGR on fetal liver.
Project description:The placenta is critical for mammalian embryonic development because the embryo’s supply of nutrients, including amino acids, depends solely on mother-to-embryo transport through the placenta. However, the molecular mechanisms underlying this amino acid supply are poorly understood. In this study, we focused on the system A amino acid transporters, Slc38a1/SNAT1, Slc38a2/SNAT2, and Slc38a4/SNAT4, which carry neutral, short-side-chain amino acids, to determine their involvement in placental or embryonic development. A triple-target CRISPR screen identified Slc38a4/SNAT4 as the critical amino acid transporter for placental development in mice. We established mouse lines from the CRISPR founders with large deletions in Slc38a4 and found that, consistent with the imprinted paternal expression of Slc38a4/SNAT4 in ther placenta, paternal knockout (KO), but not maternal KO, of Slc38a4/SNAT4 caused placental hypoplasia associated with reduced fetal weight. Immunostaining revealed that SNAT4 was widely expressed in differentiating cytotrophoblasts and maturing trophoblasts at the maternal–fetal interface. A blood metabolome analysis revealed that amino acid concentrations were globally reduced in Slc38a4/SNAT4 mutant embryos. These results indicated that, in mice, SNAT4-mediated amino acid transport plays a major role in both placental and embryonic development. Given that expression of Slc38a4 in placentas is conserved in other species, our Slc38a4/SNAT4 mutant mice could be a promising model for the analysis of placental defects leading to intrauterine growth restriction in mammals.
Project description:Vertical transmission of Zika virus (ZIKV) causes severe fetal defects, but the exact pathogenic mechanism is unclear. We identified up to a 10480-fold higher expression of viral attachment factors AXL, GAS6 and PROS1 and 3880-fold increase in ZIKV infectiousness/propagation in decidual cells (DCs) versus trophoblasts. Moreover, levels of viral attachment factors and ZIKV are significantly increased while expression of innate immune response genes are significantly decreased in first trimester versus term DCs. ZIKV-infected DC supernatants increased cytotrophoblast infection up to 252-fold compared to directly infected cytotrophoblasts. Tizoxanide treatment efficiently inhibited ZIKV infection in both cell types. We conclude that decidual cells may act as reservoirs for trimester-dependent placental transmission of ZIKV, accounting for the higher ZIKV infection susceptibility and more severe fetal sequelae observed in early versus late pregnancy. Moreover, tizoxanide is a promising agent in preventing perinatal ZIKV transmission.
