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Mild gestational hyperglycemia in rat induces fetal overgrowth and modulates placental growth factors and nutrient transporters expression.

ABSTRACT: Mild gestational hyperglycemia is often associated with fetal overgrowth that can predispose the offspring to metabolic diseases later in life. We hypothesized that unfavorable intrauterine environment may compromise the development of placenta and contribute to fetal overgrowth. Therefore, we developed a rat model and investigated the effects of maternal dysglycemia on fetal growth and placental gene expression. Female rats were treated with single injection of nicotinamide plus streptozotocin (N-STZ) 1-week before mating and were studied at gestational day 21. N-STZ pregnant females displayed impaired glucose tolerance that is associated with a lower insulin secretion. Moderate hyperglycemia induced fetal overgrowth in 40% of newborns, from pregnancies with 10 to 14 pups. The incidence of macrosomia was less than 5% in the N-STZ pregnancies when the litter size exceeds 15 newborns. We found that placental mass and the labyrinthine layer were increased in macrosomic placentas. The expression of genes involved in placental development and nutrient transfer was down regulated in the N-STZ placentas of macrosomic and normosomic pups from pregnancies with 10 to 14 ones. However, we observed that lipoprotein lipase 1 (LPL1) gene expression was significantly increased in the N-STZ placentas of macrosomic pups. In pregnancies with 15 pups or more, the expression of IGFs and glucose transporter genes was also modulated in the control placentas with no additional effect in the N-STZ ones. These data suggest that placental gene expression is modulated by gestational conditions that might disrupt the fetal growth. We described here a new model of maternal glucose intolerance that results in fetal overgrowth. We proposed that over-expression of LPL1 in the placenta may contribute to the increased fetal growth in the N-STZ pregnancies. N-STZ model offers the opportunity to determinate whether these neonatal outcomes may contribute to developmental programming of metabolic diseases in adulthood.

SUBMITTER: Cisse O

PROVIDER: S-EPMC3653871 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Mild gestational hyperglycemia in rat induces fetal overgrowth and modulates placental growth factors and nutrient transporters expression.

Cisse Ouma O Fajardy Isabelle I Dickes-Coopman Anne A Moitrot Emmanuelle E Montel Valérie V Deloof Sylvie S Rousseaux Jean J Vieau Didier D Laborie Christine C

PloS one 20130514 5

Mild gestational hyperglycemia is often associated with fetal overgrowth that can predispose the offspring to metabolic diseases later in life. We hypothesized that unfavorable intrauterine environment may compromise the development of placenta and contribute to fetal overgrowth. Therefore, we developed a rat model and investigated the effects of maternal dysglycemia on fetal growth and placental gene expression. Female rats were treated with single injection of nicotinamide plus streptozotocin ...[more]

PMID: 23691181

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Project description:Prenatal alcohol exposure (PAE) causes developmental abnormalities known as fetal alcohol spectrum disorder (FASD). Maternal iron status modulates the severity of these defects in the offspring. Because the placenta is central in supporting fetal development, we investigated whether maternal iron status similarly modulates alcohol's effects in the placenta. We hypothesized that PAE causes placental insufficiency by decreasing placental weight and efficiency, and we hypothesized that these are worsened by maternal iron deficiency (ID) and alleviated by dietary iron fortification (IF). We also determined whether altered placental iron flux and inflammatory balance contribute to placental insufficiency. Pregnant Long-Evans rats consumed an iron-deficient (ID; 2-6 ppm), iron-sufficient (IS; 100 ppm), or iron-fortified (IF; 500 ppm) diet. Alcohol (5 g/kg body weight) or isocaloric maltodextrin (MD) was gavaged daily from gestational day (GD) 13.5-19.5. Placental outcomes were evaluated on GD20.5. PAE reduced fetal weight (p < 0.0001), placental weight (p = 0.0324), and placental efficiency (p = 0.0043). PAE downregulated placental transferrin receptor (p = 0.0032); it also altered placental Il1b and Tnf expression and the Il6:Il10 ratio (p = 0.0337, 0.0300, and 0.0034, respectively) to generate a response favoring inflammation. ID-PAE further reduced fetal growth and placental efficiency and induced a heightened pro-inflammatory placental profile. IF did not rescue the alcohol-reduced fetal weight, but it normalized placental efficiency and decreased placental inflammation. These placental cytokines correlated with fetal and placental growth, and explained 45% of the variability in fetal weight and 20% of the variability in placental efficiency. In summary, alcohol induces placental insufficiency and is associated with a pro-inflammatory cytokine profile exacerbated by maternal ID and mitigated by maternal IF. Because the placenta is closely linked to intrauterine growth, the placental insufficiency reported here may correlate with the lower birth weights in a subgroup of individuals who experienced PAE.

Project description:BackgroundAdministration of progesterone (P4) to ewes during the first 9 to 12 days of pregnancy accelerates blastocyst development by day 12 of pregnancy, likely due to P4-induced up-regulation of key genes in uterine epithelia responsible for secretion and transport of components of histotroph into the uterine lumen. This study determined if acceleration of blastocyst development induced by exogenous P4 during the pre-implantation period affects fetal-placental development on day 125 of pregnancy. Suffolk ewes (n = 35) were mated to fertile rams and assigned randomly to receive daily intramuscular injections of either corn oil vehicle (CO, n = 18) or 25 mg progesterone in CO (P4, n = 17) for the first 8 days of pregnancy. All ewes were hysterectomized on day 125 of pregnancy and: 1) fetal and placental weights and measurements were recorded; 2) endometrial and placental tissues were analyzed for the expression of candidate mRNAs involved in nutrient transport and arginine metabolism; and 3) maternal plasma, fetal plasma, allantoic fluid, and amniotic fluid were analyzed for amino acids, agmatine, polyamines, glucose, and fructose.ResultsTreatment of ewes with exogenous P4 did not alter fetal or placental growth, but increased amounts of aspartate and arginine in allantoic fluid and amniotic fluid, respectively. Ewes that received exogenous P4 had greater expression of mRNAs for SLC7A1, SLC7A2, SLC2A1, AGMAT, and ODC1 in endometria, as well as SLC1A4, SLC2A5, SLC2A8 and ODC1 in placentomes. In addition, AZIN2 protein was immunolocalized to uterine luminal and glandular epithelia in P4-treated ewes, whereas AZIN2 localized only to uterine luminal epithelia in CO-treated ewes.ConclusionsThis study revealed that exogenous P4 administered in early pregnancy influenced expression of selected genes for nutrient transporters and the expression of a protein involved in polyamine synthesis on day 125 of pregnancy, suggesting a 'programming' effect of P4 on gene expression that affected the composition of nutrients in fetal-placental fluids.

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:BackgroundGestational disorders such as intrauterine growth restriction (IUGR) and pre-eclampsia (PE) are main causes of poor perinatal outcomes worldwide. Both diseases are related with impaired materno-fetal nutrient transfer, but the crucial transport mechanisms underlying IUGR and PE are not fully elucidated. In this study, we aimed to identify membrane transporters highly associated with transplacental nutrient deficiencies in IUGR/PE.ResultsIn silico analyses on the identification of differentially expressed nutrient transporters were conducted using seven eligible microarray datasets (from Gene Expression Omnibus), encompassing control and IUGR/PE placental samples. Thereby 46 out of 434 genes were identified as potentially interesting targets. They are involved in the fetal provision with amino acids, carbohydrates, lipids, vitamins and microelements. Targets of interest were clustered into a substrate-specific interaction network by using Search Tool for the Retrieval of Interacting Genes. The subsequent wet-lab validation was performed using quantitative RT-PCR on placentas from clinically well-characterized IUGR/PE patients (IUGR, n = 8; PE, n = 5; PE+IUGR, n = 10) and controls (term, n = 13; preterm, n = 7), followed by 2D-hierarchical heatmap generation. Statistical evaluation using Kruskal-Wallis tests was then applied to detect significantly different expression patterns, while scatter plot analysis indicated which transporters were predominantly influenced by IUGR or PE, or equally affected by both diseases. Identified by both methods, three overlapping targets, SLC7A7, SLC38A5 (amino acid transporters), and ABCA1 (cholesterol transporter), were further investigated at the protein level by western blotting. Protein analyses in total placental tissue lysates and membrane fractions isolated from disease and control placentas indicated an altered functional activity of those three nutrient transporters in IUGR/PE.ConclusionsCombining bioinformatic analysis, molecular biological experiments and mathematical diagramming, this study has demonstrated systematic alterations of nutrient transporter expressions in IUGR/PE. Among 46 initially targeted transporters, three significantly regulated genes were further investigated based on the severity and the disease specificity for IUGR and PE. Confirmed by mRNA and protein expression, the amino acid transporters SLC7A7 and SLC38A5 showed marked differences between controls and IUGR/PE and were regulated by both diseases. In contrast, ABCA1 may play an exclusive role in the development of PE.

Project description:BackgroundThe placenta is an essential organ that provides nutrients and oxygen to the developing fetus and removes toxic waste products from the fetal circulation. Maintaining placental blood osmotic pressure and blood flow is crucial for viable offspring. The renin-angiotensin system (RAS) in the placenta is a key player in the regulation of maternal-fetal blood flow during pregnancy. Therefore, the aim of this study was to determine if RAS genes are differentially expressed in mid to late gestation in rat placenta.MethodsWhole placental tissue samples from pregnant Sprague Dawley rats at embryonic (E) days 14.25, 15.25, 17.25 and 20 (n = 6 for each gestational age) were used for genome-wide gene expression by microarray. RAS genes with expression differences of >2 fold were further analyzed. Quantitative Real-Time PCR (qPCR) was performed on independent samples to confirm and validate microarray data. Immunohistochemisty and Western blotting were performed on a differentially expressed novel RAS pathway gene (ANPEP).ResultsSix out of 17 genes of the RAS pathway were differentially expressed at different gestational ages. Gene expression of four genes (Angiotensin converting enzyme (Ace), angiotensin converting enzyme 2 (Ace2), membrane metalloendopeptidase (Mme) and angiotensin II receptor 1A (Agtr1a)) were significantly upregulated at E20 whereas two others (Thimet oligopeptidase 1 (Thop1) and Alanyl aminopeptidase (Anpep)) were downregulated at E20 prior to the onset of labour. These changes were confirmed by qPCR. Western blots revealed no overall differences in ANPEP protein expression in the placentae. Immunohistochemical studies, however, indicated that the localization of ANPEP differed at E17.25 and E20 as ANPEP localization in the giant trophoblast cell of the junctional zone was no longer detectable at E20.ConclusionsThe current study investigated the expression of members of the RAS pathway in rat placentae and observed significantly altered expression of 6 RAS genes at 4 gestational ages. These findings present the need for further comprehensive investigation of RAS genes in normal and complicated pregnancies.

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Mild gestational hyperglycemia in rat induces fetal overgrowth and modulates placental growth factors and nutrient transporters expression.

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Mild gestational hyperglycemia in rat induces fetal overgrowth and modulates placental growth factors and nutrient transporters expression.

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