Dataset Information

MiRNAs as common regulators of the transforming growth factor (TGF)-β pathway in the preeclamptic placenta and cadmium-treated trophoblasts: Links between the environment, the epigenome and preeclampsia.

ABSTRACT: Preeclampsia (PE) is a pregnancy disorder characterized by high blood pressure and proteinuria that can cause adverse health effects in both mother and fetus. There is no current cure for PE other than delivery of the fetus/placenta. While the etiology is unknown, poor placentation due to aberrant signaling of growth and angiogenic factors has been postulated as a causal factor of PE. In addition, environmental contaminants, such as the metal cadmium (Cd), have been linked to placental toxicity and increased risk of developing PE. Here, we use a translational study design to investigate genomic and epigenomic alterations in both placentas and placental trophoblasts, focused on the angiogenesis-associated transforming growth factor-beta (TGF-β) pathway. Genes within the TGF-β pathway displayed increased expression in both the preeclamptic placenta and Cd-treated trophoblasts. In addition, miRNAs that target the TGF-β pathway were also significantly altered within the preeclamptic placenta and Cd-treated trophoblasts. Integrative analysis resulted in the identification of a subset of Cd-responsive miRNAs, including miR-26a and miR-155, common to preeclamptic placentas and Cd-treated trophoblasts. These miRNAs have previously been linked to PE and are predicted to regulate members of the TGF-β pathway. Results from this study provide future targets for PE treatment.

SUBMITTER: Brooks SA

PROVIDER: S-EPMC5156314 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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miRNAs as common regulators of the transforming growth factor (TGF)-β pathway in the preeclamptic placenta and cadmium-treated trophoblasts: Links between the environment, the epigenome and preeclampsia.

Brooks Samira A SA Martin Elizabeth E Smeester Lisa L Grace Matthew R MR Boggess Kim K Fry Rebecca C RC

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 20160629 Pt A

Preeclampsia (PE) is a pregnancy disorder characterized by high blood pressure and proteinuria that can cause adverse health effects in both mother and fetus. There is no current cure for PE other than delivery of the fetus/placenta. While the etiology is unknown, poor placentation due to aberrant signaling of growth and angiogenic factors has been postulated as a causal factor of PE. In addition, environmental contaminants, such as the metal cadmium (Cd), have been linked to placental toxicity ...[more]

PMID: 27375191

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Project description:BackgroundWe have demonstrated that protein aggregation plays a pivotal role in the pathophysiology of preeclampsia and identified several aggregated proteins in the circulation of preeclampsia patients, the most prominent of which is the serum protein TTR (transthyretin). However, the mechanisms that underlie protein aggregation remain poorly addressed.MethodsWe examined TTR aggregates in hypoxia/reoxygenation-exposed primary human trophoblasts (PHTs) and the preeclampsia placenta using complementary approaches, including a novel protein aggregate detection assay. Mechanistic analysis was performed in hypoxia/reoxygenation-exposed PHTs and Ttr transgenic mice overexpressing transgene-encoded wild-type human TTR or Ttr-/- mice. High-resolution ultrasound analysis was used to measure placental blood flow in pregnant mice.ResultsTTR aggregation was inducible in PHTs and the TCL-1 trophoblast cell line by endoplasmic reticulum stress inducers or autophagy-lysosomal disruptors. PHTs exposed to hypoxia/reoxygenation showed increased intracellular BiP (binding immunoglobulin protein), phosphorylated IRE1α (inositol-requiring enzyme-1α), PDI (protein disulfide isomerase), and Ero-1, all markers of the unfolded protein response, and the apoptosis mediator caspase-3. Blockade of IRE1α inhibited hypoxia/reoxygenation-induced upregulation of Ero-1 in PHTs. Excessive unfolded protein response activation was observed in the early-onset preeclampsia placenta. Importantly, pregnant human TTR mice displayed aggregated TTR in the junctional zone of the placenta and severe preeclampsia-like features. High-resolution ultrasound analysis revealed low blood flow in uterine and umbilical arteries in human TTR mice compared with control mice. However, Ttr-/- mice did not show any pregnancy-associated abnormalities.ConclusionsThese observations in the preeclampsia placenta, cultured trophoblasts, and Ttr transgenic mice indicate that TTR aggregation is an important causal contributor to preeclampsia pathophysiology.

Project description:BackgroundPreeclampsia (PE) is a hypertensive pregnancy disorder linked to placental dysfunction, often involving pathological lesions like acute atherosis, decidual vasculopathy, accelerated villous maturation, and fibrinoid deposition. However, there is no gold standard for the pathological diagnosis of PE and this limits the ability of clinicians to distinguish between PE and non-PE pregnancies. Recent advances in computational pathology have provided the opportunity to automate pathological analysis for diagnosis, classification, prediction, and prediction of disease progression. In this study, we assessed whether computational pathology could be used to identify PE placentas.MethodsA total of 168 placental whole-slide images (WSIs) of patients from Seoul National University Hospital (comprising 84 PE cases and 84 normal controls) were used for model development and internal validation. For external validation of the model, 76 placental slides (including 38 PE cases and 38 normal controls) were obtained from the Boramae Medical Center (BMC). To establish standard criteria for diagnosing PE and distinguishing it from controls using placental WSIs, patch characteristics and quantification of terminal and intermediate villi were employed. In unsupervised learning, K-means clustering was conducted as a feature obtained through an Auto Encoder to extract the ratio of each cluster for each WSI. For supervised learning, quantitative assessments of the villi were obtained using a U-Net-based segmentation algorithm. The prediction model was developed using an ensemble method and was compared with a clinical feature model developed by using placental size features.ResultsUsing ensemble modeling, we developed a model to identify PE placentas. The model showed good performance (area under the precision-recall curve [AUPRC], 0.771; 95% confidence interval [CI], 0.752-0.790), with 77.3% of sensitivity and 71.1% of specificity, whereas the clinical feature model showed an AUPRC 0.713 (95% CI, 0.694-0.732) with 55.6% sensitivity and 86.8% specificity. External validation of the predictive model employing the BMC-derived set of placental slides also showed good discrimination (AUPRC, 0.725; 95% CI, 0.720-0.730).ConclusionThe proposed computational pathology model demonstrated a strong ability to identify preeclamptic placentas. Computational pathology has the potential to improve the identification of PE placentas.

Dataset Information

MiRNAs as common regulators of the transforming growth factor (TGF)-β pathway in the preeclamptic placenta and cadmium-treated trophoblasts: Links between the environment, the epigenome and preeclampsia.

Publications

miRNAs as common regulators of the transforming growth factor (TGF)-β pathway in the preeclamptic placenta and cadmium-treated trophoblasts: Links between the environment, the epigenome and preeclampsia.

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