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RNA-seq analysis of the rat placentation site reveals maternal obesity-associated changes in placental and offspring thyroid hormone signaling.

ABSTRACT: In animal models, maternal obesity (OB) leads to augmented risk of offspring OB. While placental function is influenced by maternal habitus, the effect of maternal obesity on the interacting zones of the placenta [the labyrinth (LZ), junctional (JZ) and metrial gland (MG)] remains unknown.Using a rat maternal obesity model, we conducted transcriptomic profiling of the utero-placental compartments and fetal liver (FL) at dpc 18.5, in conjunction with analyses of mRNA expression of key thyroid hormone (TH) signaling genes in the placenta, fetus and weanling offspring.Gene expression analysis of placenta and offspring revealed that each utero-placental compartment responds distinctly to maternal OB with changes in inflammatory signaling, lipid metabolism and hormone stimulus being the predominant effects. OB-induced alterations in 17 genes were confirmed by qPCR, including reductions in thyrotropin-releasing hormone (Trh) in JZ. We further characterized mRNA and protein expression of TH signaling regulators including deiodinases (Dio), TH receptors (Tr), and downstream targets (uncoupling proteins (Ucp)). A concerted down-regulation of multiple facets of thyroid hormone signaling in the JZ and FL was observed. JZ expression of thyroid hormone signaling components Trh, Dio2, Tr?, and Ucp2 were negatively associated with maternal leptin. mRNA expression of TRH, TR? and UCP1 were also decreased in term placenta from OB women. Finally, our studies identified persistent impairments in expression of TH related genes in tissues from offspring of obese dams.The role of lower placental thyroid expression is worthy of further study as a possible pathway that leads to low energy metabolism and obesity in animals born to obese mothers.

SUBMITTER: Saben J

PROVIDER: S-EPMC4270847 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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RNA-seq analysis of the rat placentation site reveals maternal obesity-associated changes in placental and offspring thyroid hormone signaling.

Saben J J Kang P P Zhong Y Y Thakali K M KM Gomez-Acevedo H H Borengasser S J SJ Andres A A Badger T M TM Shankar K K

Placenta 20141005 12

<h4>Introduction</h4>In animal models, maternal obesity (OB) leads to augmented risk of offspring OB. While placental function is influenced by maternal habitus, the effect of maternal obesity on the interacting zones of the placenta [the labyrinth (LZ), junctional (JZ) and metrial gland (MG)] remains unknown.<h4>Methods</h4>Using a rat maternal obesity model, we conducted transcriptomic profiling of the utero-placental compartments and fetal liver (FL) at dpc 18.5, in conjunction with analyses ...[more]

PMID: 25449029

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Project description:Importance:Hypothyroidism during pregnancy is associated with neurodevelopmental delays in the offspring. However, it remains unknown whether prenatal thyroid hormone replacement therapy (THRT) has benefits regarding children's language and communication skills. Objective:To quantify associations between prenatal THRT exposure and risk of language impairment diagnosis and parent-reported symptoms of language and communication skill deficits in offspring at 8 years of age. Design, Setting, and Participants:The Norwegian Mother, Father and Child Cohort Study (MoBa), a nationwide population-based cohort study, recruited pregnant women from throughout Norway between June 1999 and December 2008. MoBa was linked to several nationwide registries: the Norwegian Medical Birth Registry, Norwegian Prescription Database, and Norwegian Patient Registry. For this study, the analyzed cohort was restricted to singleton pregnancies resulting in a live-born infant, enrolled in the MoBa between 2005 and 2008. Statistical analysis was performed from January 2 to May 7, 2019. Exposures:In both study samples, mother-child pairs were categorized into 3 mutually exclusive groups: THRT exposure during pregnancy, based on dispensed prescription records; unexposed to THRT during pregnancy (population comparison); and mothers initiating THRT after delivery (THRT after delivery), comprising incident postpartum THRT users. Main Outcomes and Measures:Two defined study samples were analyzed with different outcome measures. In the Norwegian Patient Registry sample, outcome was defined by a diagnosis of language and speech impairment. In the MoBa sample, children were followed up until age 8 years via parental self-completed questionnaires. Hazard ratios were calculated for language impairment diagnosis, estimated by Cox proportional hazards regression. Standardized mean score (β) was calculated for parent-reported symptoms of language and communication deficits, estimated using generalized linear models. Results:The Norwegian Patient Registry sample included 53 862 mother-child pairs (mean [SD] age, 30.4 [4.6] years; offspring, 26 145 girls and 27 717 boys; 1204 pairs exposed to THRT [2.2%]) and the MoBa sample included 23 686 mother-child pairs (mean [SD] age, 30.8 [4.4] years; offspring, 11 536 girls and 12 150 boys; 532 pairs exposed to THRT [2.2%]). Language and speech impairment diagnosis was not significantly associated with prenatal THRT exposure compared with the unexposed group (adjusted hazard ratio, 0.75; 95% CI, 0.38-1.43) or the THRT after delivery group (adjusted hazard ratio, 0.63; 95% CI, 0.26-1.53). Language outcomes also did not significantly differ between these groups. Conclusions and Relevance:There was no significant difference in child outcomes between children exposed to THRT in the prenatal period compared with children in the population comparison group. These results support current guidelines recommending hypothyroidism treatment during pregnancy. Future research should further examine the use of THRT after delivery or a proper disease comparison group.

Project description:BACKGROUND:In the last 2 decades, several studies have examined the association between maternal thyroid hormone insufficiency during pregnancy and neurodevelopmental disorders in children and shown conflicting results. AIM:This systematic review aimed to assess the evidence for an association between maternal thyroid hormone insufficiency during pregnancy and neurodevelopmental disorders in children. We also sought to assess whether levothyroxine treatment for maternal thyroid hormone insufficiency improves child neurodevelopment outcomes. METHODS:We performed systematic literature searches in MEDLINE, EMBASE, PSYCinfo, CINAHL, AMED, BNI, Cochrane, Scopus, Web of Science, GreyLit, Grey Source and Open Grey (latest search: March 2017). We also conducted targeted web searching and performed forwards and backwards citation chasing. Meta-analyses of eligible studies were carried out using the random-effects model. RESULTS:We identified 39 eligible articles (37 observational studies and 2 randomized controlled trials [RCT]). Meta-analysis showed that maternal subclinical hypothyroidism and hypothyroxinaemia are associated with indicators of intellectual disability in offspring (odds ratio [OR] 2.14, 95% confidence interval [CI] 1.20 to 3.83, P = .01, and OR 1.63, 95% CI 1.03 to 2.56, P = .04, respectively). Maternal subclinical hypothyroidism and hypothyroxinaemia were not associated with attention deficit hyperactivity disorder, and their effect on the risk of autism in offspring was unclear. Meta-analysis of RCTs showed no evidence that levothyroxine treatment for maternal hypothyroxinaemia or subclinical hypothyroidism reduces the incidence of low intelligence quotient in offspring. LIMITATIONS:Although studies were generally of good quality, there was evidence of heterogeneity between the included observational studies (I2 72%-79%). CONCLUSION:Maternal hypothyroxinaemia and subclinical hypothyroidism may be associated with intellectual disability in offspring. Currently, there is no evidence that levothyroxine treatment, when initiated 8- to 20-week gestation (mostly between 12 and 17 weeks), for mild maternal thyroid hormone insufficiency during pregnancy reduces intellectual disability in offspring.

Project description:The risk of obesity (OB) in adulthood is strongly influenced by maternal body composition. Here we examined the hypothesis that maternal OB influences white adipose tissue (WAT) transcriptome and increases propensity for adipogenesis in the offspring, prior to the development of OB, using an established model of long-term metabolic programming. Employing an overfeeding-based rat model, in which exposure to OB is limited to preconception and gestation alone, we conducted global transcriptomic profiling in WAT, and gene/protein expression analysis of lipogenic and adipogenic pathways and examined adipogenic differentiation of WAT stromal-vascular cells ex vivo. Using reduced representation bisulfite sequencing we also evaluated genome-scale changes in DNA methylation in offspring WAT. Maternal OB led to extensive changes in expression of genes (± 1.8-fold, P ? .05), revealing a distinct up-regulation of lipogenic pathways in WAT. mRNA expression of a battery of sterol regulatory element-binding protein-1-regulated genes was increased in OB-dam offspring, which were confirmed by immunoblotting. In conjunction with lipogenic gene expression, OB-dam offspring showed increased glucose transporter-4 mRNA/protein expression and greater AKT phosphorylation following acute insulin challenge, suggesting sensitization of insulin signaling in WAT. Offspring of OB dams also exhibited increased in vivo expression of adipogenic regulators (peroxisome proliferator-activated receptor-?, CCAAT enhancer binding protein ? [C/EBP-?] and C/EBP-?), associated with greater ex vivo differentiation of WAT stromal-vascular cells. These transcriptomic changes were associated with alterations in DNA methylation of CpG sites and CGI shores, proximal to developmentally important genes, including key pro-adipogenic factors (Zfp423 and C/EBP-?). Our findings strongly suggest that the maternal OB in utero alters adipocyte commitment and differentiation via epigenetic mechanisms.

Project description:Maternal high-fat diet consumption predisposes to metabolic and liver dysfunction in F1 male and female at young adulthood. Purpose: We used RNA-seq to determine the liver transcriptome of male and female F1 of MO and control fed mothers. Methods: Female Wistar rat mothers ate control (C) or obesogenic (MO) diet from the time they were weaned through breeding at postnatal day (PND) 120, delivery and lactation. After weaning all male and female F1 ate control diet. At PND 110 liver and fat were collected to analyze metabolites, histology and liver differentially expressed genes. To identify the functional F1 liver changes due to MO, we evaluated the differentially expressed genes (DEGs) between MO and C males and females with separate pairwise comparisons due to the marked differences between males and females. Genes were filtered based on ≥ 1.4 fold change (FC) and nominal P value <0.05 (Student´s t-test). Results: MOF1 males presented greater physiologic and histological NAFLD characteristics than MOF1 females. RNA-seq revealed 1,365 genes significantly changed in male MOF1 liver and only 70 genes in MOF1 female compared with controls. GO and KEGG analysis identified differentially expressed genes related to metabolic process. Male MOF1 liver showed the following altered pathways: insulin signaling (22 genes), phospholipase D signaling (14 genes), NAFLD (13 genes), and glycolysis/ gluconeogenesis (7 genes). In contrast, few genes were altered in these pathways in MOF1 females. Conclusions: These results improve understanding of the mechanism by which a maternal high fat diet affects their F1. In summary, MO programs sex-dependent F1 changes in insulin, glucose and lipid signaling pathways, leading to liver dysfunction and insulin resistance. Male adult MOF1 livers show global down-regulation of genes that are required for normal function of major liver metabolic pathways. This new knowledge is important for producing sex-specific interventions.

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RNA-seq analysis of the rat placentation site reveals maternal obesity-associated changes in placental and offspring thyroid hormone signaling.

Publications

RNA-seq analysis of the rat placentation site reveals maternal obesity-associated changes in placental and offspring thyroid hormone signaling.

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