Maternal Bisphenol A effect on fetal heart and skeletal muscle gene expression
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ABSTRACT: Compairsion of transcriptional profiles of heart and skeletal muscle tissue of fetal rhesus monkey exposed to maternal Bisphenol A or vehicle during early or late gestaion. Maternal exposure to the endocrine disrupting chemical, bisphenol A (BPA) affects the development of multiple organ systems in rodents and monkeys. However, effects of BPA exposure on cardiac and skeletal muscle development have not been assessed. Given that maternal BPA crosses placenta and reaches developing fetus, examining the physiological consequences of gestational exposure during development is of research significance. Therefore, we evaluate the effects of daily, oral BPA exposure of pregnant rhesus monkeys (Macaca mulatta) on the fetal heart and skeletal muscle transcriptome. Pregnant monkeys were administered daily oral doses (400 M-BM-5g/kg body weight) of BPA during early (50 M-bM-^@M-^S100 M-BM-1 2 days post conception, dpc) or late (100 M-BM-1 2 dpc - term), gestation. At the end of treatment, fetal heart tissues; left ventricle (LV), right ventricle (RV), left atrium (LA), right atrium (RA) and skeletal muscle; biceps femoris (BFM), were collected. Transcriptome expression was assessed using genome-wide microarray in each of the tissues and compared paired-wise between the BPA and matched control fetuses. Our results show that maternal BPA exposure alters transcriptional profile of several coding and non-coding genes in fetal heart and skeletal muscle. Pregnant rhesus monkey were administered a daily oral dose of 400 M-NM-
Project description:Compairsion of transcriptional profiles of heart and skeletal muscle tissue of fetal rhesus monkey exposed to maternal Bisphenol A or vehicle during early or late gestaion. Maternal exposure to the endocrine disrupting chemical, bisphenol A (BPA) affects the development of multiple organ systems in rodents and monkeys. However, effects of BPA exposure on cardiac and skeletal muscle development have not been assessed. Given that maternal BPA crosses placenta and reaches developing fetus, examining the physiological consequences of gestational exposure during development is of research significance. Therefore, we evaluate the effects of daily, oral BPA exposure of pregnant rhesus monkeys (Macaca mulatta) on the fetal heart and skeletal muscle transcriptome. Pregnant monkeys were administered daily oral doses (400 µg/kg body weight) of BPA during early (50 –100 ± 2 days post conception, dpc) or late (100 ± 2 dpc - term), gestation. At the end of treatment, fetal heart tissues; left ventricle (LV), right ventricle (RV), left atrium (LA), right atrium (RA) and skeletal muscle; biceps femoris (BFM), were collected. Transcriptome expression was assessed using genome-wide microarray in each of the tissues and compared paired-wise between the BPA and matched control fetuses. Our results show that maternal BPA exposure alters transcriptional profile of several coding and non-coding genes in fetal heart and skeletal muscle.
Project description:To characterize a expression patterns in the heart, we used rat. 12 Wistar male rats (8 - 11 weeks) were sacrificed. Left atrium (LA) adjacent to the pulmonary vein (PV), a mass of left ventricle (LV), and free-wall of the right ventricle (RV) was isolated. Each LV mass was dissected into three pieces as samples. Because the SAN isolation procedure takes approximately 20 minutes, SA was isolated separately. The SA region was delimited by the borders of the crista terminalis, the interatrial septum, the superior vena cava, and right atrium (RA). In addition to PV, LV, RV, SA, and RA samples, pulmonary arteries were added to the samples for the rat microarray.
Project description:Background: Lamins A/C (encoded by the LMNA gene) can lead to dilated cardiomyopathy (DCM). Objectives: This study sought to undertake proteomic analysis of myocardial tissue to explore the postgenomic phenotype of end-stage lamin heart disease. Methods: Consecutive patients with end-stage lamin heart disease (LMNA-group, n=7) and ischaemic DCM (ICM-group, n=7) undergoing heart transplantation were enrolled. Samples were obtained from left atrium(LA), left ventricle(LV), right atrium(RA), right ventricle(RV) and interventricular septum(IVS). Liquid chromatography combined with mass-spectrometry was used for protein quantification. We compared protein concentrations in cardiac samples between LMNA and ICM groups. Proteins were considered differentially abundant if the quantitative difference was 1.5-fold and corrected p-value <0.05 at a false discovery rate of 0.01. Gene ontology(GO) enrichment analysis explored the related biological processes. Results: 4,247 proteins were identified in LMNA and ICM samples, of which 633 were differentially abundant in LA, 39 in LV, 181 in RA, 52 in RV, and 85 in IVS. Abundance of lamin A/C was reduced but lamin B (LMNB) increased in LMNA LA/RA tissue compared to ICM, but not in LV/RV. Transthyretin was more abundant in the LV/RV of LMNA compared to ICM while sarcomeric proteins such as titin and cardiac myosin heavy chain were generally reduced in RA/LA of LMNA. Protein expression profiling and GO enrichment analysis revealed sarcopenia, extracellular matrix(ECM) remodeling, deficient myocardial energetics, redox imbalances, and abnormal calcium handling in LMNA samples. Conclusion: Lamin heart disease is a biventricular and biatrial disease, characterized by sarcopenia, aberrant metabolism, and ECM remodeling. LMNB and transthyretin were unexpectedly abundant in the atria and ventricles respectively of patients with end-stage lamin heart disease potentially hinting to the possibility of compensatory responses.
Project description:An Infinium microarray platform (GPL28271, HorvathMammalMethylChip40) was used to generate DNA methylation data from many tissues from horses We generated DNA methylation data from n=333 horse tissue samples representing tissues. Blood samples were collected via venipuncture into EDTA tubes from across 24 different horse breeds (buffy coat). The other tissues were collected at necropsy. The tissue atlas was generated from two Thoroughbred mares as part of the FAANG initiative 37, with the following tissues profiled: adipose (gluteal), adrenal cortex, blood (PBMCs; only n=1 mare), cartilage (only n=1 mare), cecum, cerebellum (2 samples each from lateral hemisphere and vermis), frontal cortex, duodenum, fibroblast, heart (2 samples each from the right atrium, left atrium, right ventricle, left ventricle), hypothalamus, ileum, jejunum, keratinocyte, kidney (kidney cortex and medulla), lamina, larynx (i.e. cricoarytenoideus dorsalis muscle), liver, lung, mammary gland, mitral valve of the heart, skeletal muscle (gluteal muscle and longissimus muscle), occipital cortex, ovary, parietal cortex, pituitary, sacrocaudalis dorsalis muscle, skin, spinal cord (C1 and T8), spleen, suspensory ligament, temporal cortex, tendon (deep digital flexor tendon and superficial digital flexor tendon), uterus.
Project description:Pulmonary arterial hypertension (PAH) is characterized by remodelling of the pulmonary arteries and right ventricle (RV), which leads to functional decline of cardiac and skeletal muscle. This study investigated the effects of a multi-targeted nutritional intervention with extra protein, leucine, fish oil and oligosaccharides on cardiac and skeletal muscle in PAH. PAH was induced in female C57BL/6 mice by weekly injections of monocrotaline (MCT) for 8 weeks. Control diet (sham and MCT group) and isocaloric nutritional intervention (MCT + NI) were administered. Compared to sham, MCT mice increased heart weight by 7%, RV thickness by 13% and fibrosis by 60% (all p < 0.05) and these were attenuated in MCT + NI mice. Microarray and qRT-PCR analysis of RV confirmed effects on fibrotic pathways. Skeletal muscle fiber atrophy was induced (P < 0.05) by 22% in MCT compared to sham mice, but prevented in MCT + NI group. Our findings show that a multi-targeted nutritional intervention attenuated detrimental alterations to both cardiac and skeletal muscle in a mouse model of PAH, which provides directions for future therapeutic strategies targeting functional decline of both tissues.
Project description:Identification of genome-wide PRDM16 binding sites in E13.5 whole mouse heart, as well as in isolated left ventricle (LV) and right ventricle (RV).
Project description:This research aimed to identify protein biomarkers of right ventricular dysfunction in patients with advanced heart failure with reduced ejection fraction (HFrEF). Samples of myocardium from both, right and left ventricles (RV, LV) were obtained from 10 HFrEF patients with right ventricular dysfunction (RVD), 10 HFrEF patients without RVD (noRVD) undergoing heart transplantation, and 10 non-failing unused donor hearts (Control). Tissue samples were homogenized and extracted using mild Triton X-100 detergent and processed by SP3 extraction to remove the detergent prior the analysis, (LFQ) proteomic analysis identified a total of 4 032 proteins in the left ventricle and 3 788 proteins in the right ventricle.
Project description:Right ventricular (RV) failure plays a critical role in any type of heart failure. However, there is no specific therapy developed for RV failure. To understand RV failure, we focused on the RV specific genes. Global gene expression analysis showed that alternative complement pathway-related genes including C3 and Cfd were significantly upregulated in right ventricle in murine heart. We generated the RV failure by right ventricle-specific pressure overload model mice, pulmonary artery constriction (PAC), which induces RV failure around 14 days. In C3 knockout (C3KO) mice, PAC-induced RV dysfunction and fibrosis were significantly attenuated. C3a is produced from C3 by C3 convertase complex including Cfd. Cfd knockout mice also attenuated PAC-induced RV failure. Moreover, C3a receptor (C3aR) antagonist dramatically improved PAC-induced RV dysfunction in wild type mice. Here we revealed the crucial role of C3-Cfd-C3a-C3aR axis in RV failure and highlight the potential therapeutic target for RV failure with no pharmacologic option.
Project description:Gene expression profiling in whole heart, left ventricle (LV) and right ventricle (RV) of WT and Prdm16 conditional knockout (Prdm16cKO) mouse (Prdm16flox/flox; Xmlc2-Cre) at embryonic day 13.5 (E13.5).
Project description:Right ventricular (RV) failure plays a critical role in any type of heart failure. However, there is no specific therapy developed for RV failure. To understand RV failure, we focused on the RV specific genes. Global gene expression analysis showed that alternative complement pathway-related genes including C3 and Cfd were significantly upregulated in right ventricle in murine heart. We generated the RV failure by right ventricle-specific pressure overload model mice, pulmonary artery constriction (PAC), which induces RV failure around 14 days. After administration of C3a receptor (C3aR) antagonist, RV function was dramatically improved PAC-induced RV dysfunction in wild type mice. To investigate the role of C3a to cardiomyocyte, C3a recombinant protein was administerd to neonatal rat ventricular myocytes (NRVMs), the results that several MAP kinesis were phosphorylated by C3a. In turn, to identify the key expressed genes as downstream of C3a in NRVMs, global gene expression analysis was performed in vitro.