Biomarkers for Placental Abnormality

Obstetrical complications including recurrent miscarriage, pre-eclampsia and intrauterine growth restriction (IUGR) affect 1%-5% of pregnant women (Younis and Samueloff 2003). Dysfunctional trophoblasts, impaired development of spiral arteries, imbalance in systems controlling the dilation and contraction of spiral arteries, placental fibrin clots and intervillous thrombosis are all possible factors that can result in an insufficient placental circulation. The combination of the hypercoagulable state of pregnancy and presence of genetic thrombophilic markets has the potential to induce placental thrombosis and cause placental insufficiency with subsequent obstetrical complications. The initial part of the research work involved examining the relationship between four common genetic risk factors for thrombosis in a recurrent miscarriage cohort using multiplex ARMS PCR. The result of phenotypic assays (activated protein C resistance, protein C levels, protein S levels, FVIII levels) for the recurrent miscarriage cohort were examined. There was no increased prevalence of any of the four genetic risk factors for thrombosis in our recurrent miscarriage cohort. Following examination of phenotypic assay results there was no concise link to recurrent miscarriage. The next phase of the work required the application of the multiplex ARMS PCR to cohorts IUGR and normal pregnancy placental samples. Our results indicated that none of the four genetic risk factors for thrombosis had an increased prevalence in the IUGR cohort compared with the normal pregnancy cohort. These results imply that for our two cohorts of obstetric complications, genetic risk factors predisposing to thrombosis, do not increase the risk of developing obstetrical complications. In our second set of experiments we investigated if inflammation is a potential contributor to placental insufficiency by disrupting the homeostasis of the uteroplacental circulation. A selection of inflammatory and haemostatic markers in IUGR and normal pregnancy cohorts were assessed using immunohistochemistry. Our results indicated no difference in expression of either inflammatory or haemostatic markets between the two cohorts. We also evaluated the proliferative and apoptotic status in both normal and IUGR cohorts. These results indicated a decrease in proliferation and an increase in apoptosis in the IUGR cohort compared to the normal cohort, suggesting a decline in the quality of functional trophoblasts in the IUGR placentas. The main aim of the final portion of the research was to examine the molecular aetiology of IUGR using microarray technology. This technology allows the evaluation of expression of thousands of genes on one single microarray chip. Following microarray analysis 293 genes had a two-fold difference in expression between a normal pregnancy cohort and an IUGR cohort. This list was reduced to the ten most significantly expressed genes between the two cohorts. Leptin and sFlt-1 receptor are two of the genes involved, these genes are associated with appetite control, angiogenesis and vessel growth. Until now our understanding of the various factors involved in defective placentation resulting in obstetrical complications has been limited. The findings of this thesis have determined the status of certain factors in obstetric complications while also discovering potentially novel components and mechanisms involved in the pathogenesis of IUGR

Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia

Aberrant placentation generating placental oxidative stress is proposed to play a critical role in the pathophysiology of preeclampsia. Unfortunately, therapeutic trials of antioxidants have been uniformly disappointing. There is provisional evidence implicating mitochondrial dysfunction as a source of oxidative stress in preeclampsia. Here we provide evidence that mitochondrial reactive oxygen species mediates endothelial dysfunction and establish that directly targeting mitochondrial scavenging may provide a protective role. Human umbilical vein endothelial cells exposed to 3% plasma from women with pregnancies complicated by preeclampsia resulted in a significant decrease in mitochondrial function with a subsequent significant increase in mitochondrial superoxide generation compared to cells exposed to plasma from women with uncomplicated pregnancies. Real-time PCR analysis showed increased expression of inflammatory markers TNF-α, TLR-9 and ICAM-1 respectively in endothelial cells treated with preeclampsia plasma. MitoTempo is a mitochondrial-targeted antioxidant, pre-treatment of cells with MitoTempo protected against hydrogen peroxide-induced cell death. Furthermore MitoTempo significantly reduced mitochondrial superoxide production in cells exposed to preeclampsia plasma by normalising mitochondrial metabolism. MitoTempo significantly altered the inflammatory profile of plasma treated cells. These novel data support a functional role for mitochondrial redox signaling in modulating the pathogenesis of preeclampsia and identifies mitochondrial-targeted antioxidants as potential therapeutic candidates

Mitochondrial [dys]function; culprit in pre-eclampsia?

Mitochondria are extensively identified for their bioenergetic capacities; however, recently these metabolic hubs are increasingly being appreciated as critical regulators of numerous cellular signalling systems. Mitochondrial reactive oxygen species have evolved as a mode of cross-talk between mitochondrial function and physiological systems, to sustain equipoise and foster adaption to cellular stress. Redox signalling mediated by exaggerated mitochondrial-ROS (reactive oxygen species) has been incriminated in a plethora of disease pathologies. Excessive production of mitochondrial ROS is intrinsically linked to mitochondrial dysfunction. Furthermore, mitochondrial dysfunction is a key facilitator of oxidative stress, inflammation, apoptosis and metabolism. These are key pathogenic intermediaries of pre-eclampsia, hence we hypothesize that mitochondrial dysfunction is a pathogenic mediator of oxidative stress in the pathophysiology of pre-eclampsia. We hypothesize that mitochondrial-targeted antioxidants may restrain production of ROS-mediated deleterious redox signalling pathways. If our hypothesis proves correct, therapeutic strategies directly targeting mitochondrial superoxide scavenging should be actively pursued as they may alleviate maternal vascular dysfunction and dramatically improve maternal and fetal health worldwide

Oxidative stress in pre-eclampsia; have we been looking in the wrong place?

Pre-eclampsia is a disorder of late pregnancy. It is a major cause of maternal and perinatal morbidity and mortality, accounting for nearly 18% of all maternal deaths worldwide; an estimated 77,000 maternal deaths per year [1]. Poor placentation is considered to be an initial cause of the placental ischemia [2]. Placental ischemia in turn gives rise to oxidative stress in the placenta and leads to shedding of syncytiotrophoblast debris into the maternal circulation provoking a systemic maternal inflammatory response and release of sFLT and sENG causing maternal vascular endothelial dysfunction. The ubiquitous nature of the maternal vascular endothelium accounts for the diverse multi-system nature of pre-eclampsia. Currently there is no treatment for pre-eclampsia except delivery of the placenta and the baby, with the attendant risk of iatrogenic prematurity and significant neonatal morbidity and mortality. As a result, intensive research endeavours have focused on defining the molecular mechanisms of pre-eclampsia and the identification of new pre-symptomatic biomarkers of the condition. This review focuses on the role of elevated oxidative stress in the pathology of pre-eclampsia and potential therapeutic agents targeting oxidative stress that may prevent or ameliorate this disorder

Investigating mitochondrial dysfunction in gestational diabetes mellitus and elucidating if BMI is a causative mediator

Objective: Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance which is diagnosed during pregnancy and poses considerable health risks for mother and child. Maternal body mass index (BMI) correlates with GDM diagnosis and the pathophysiology of this link may be explained through oxidative stress and mitochondrial dysfunction. In this study we investigate if mitochondrial dysfunction is evident in GDM by measuring cell free mitochondrial DNA concentration and determine if a potential relationship exists between maternal mitochondrial function and GDM diagnosis. Study design: Plasma samples were taken at 20 weeks' gestation from women who subsequently developed GDM (n = 44) and matched with women with uncomplicated pregnancies (n = 85) as controls. Control group 1 was matched by maternal age and BMI (n = 41) to GDM cases, while control group 2 was matched by maternal age alone (n = 44). Prediction potential was determined by binary regression analysis. Statistical analysis was performed on SPSS Statistics v25. Results: Binary regression analysis showed a statistically significant association between mtDNA concentration and GDM diagnosis (p = 0.032) in GDM cases versus control group 2, indicating that GDM patients have higher circulating mtDNA concentrations relative to healthy control patients. The lack of statistical significance in control group 1 suggests that BMI may be linked to mitochondrial function in GDM patients. Conclusion: These results demonstrate a potential pathogenic role for mitochondrial dysfunction in GDM, with BMI presenting as a likely physiological mediator

A perspective on pre-eclampsia and neurodevelopmental outcomes in the offspring: Does maternal inflammation play a role?

Pre-eclampsia is a leading cause of maternal death and maternal and perinatal morbidity. Whilst the clinical manifestations of pre-eclampsia often occur in late pregnancy, the molecular events leading into the onset of this disease are thought to originate in early pregnancy and result in insufficient placentation. Although the causative molecular basis of pre-eclampsia remains poorly understood, maternal inflammation is recognised as a core clinical feature. While the adverse effects of pre-eclampsia on maternal and fetal health in pregnancy is well-recognised, the long-term impact of pre-eclampsia exposure on the risk of autism spectrum disorder (ASD) in exposed offspring is a topic of on-going debate. In particular, a recent systematic review has reported an association between exposure to pre-eclampsia and increased risk of ASD, however the molecular basis of this association is unknown. Here we review recent evidence for; 1) maternal inflammation in pre-eclampsia; 2) epidemiological evidence for alterations in neurodevelopmental outcomes in offspring exposed to pre-eclampsia; 3) long-term changes in the brains of offspring exposed to pre-eclampsia; and 4) how maternal inflammation may lead to altered neurodevelopmental outcomes in pre-eclampsia exposed offspring. Finally, we discuss the implications of this for the development of future studies in this field

Teagasc submission made in response to the Consultation Paper on Interim Review of Ireland’s Nitrates Derogation 2019

Teagasc SubmissionSubmission to governmentThis submission was made in response to the consultation process run jointly by the Department of Housing, Planning, Community and Local Government (DHPCLG) and the Department of Agriculture, Food and the Marine (DAFM) inviting views and comments on proposals for the Interim Review of Ireland’s Nitrates Derogation Programme in 2019. It has been prepared by Teagasc’s Water Quality Working Group in consultation with the Gaseous Emissions Working Group. These working groups have members drawn from both the Knowledge Transfer and Research Directorates of Teagasc. It was prepared following consultation with colleagues across Teagasc using their collective knowledge and expertise in agri-environmental science and practice and the implementation of the Good Agricultural Practice (GAP) and Nitrates Derogation Regulations.https://www.teagasc.ie/publications/2019/teagasc-submission-made-in-response-to-the-consultation-paper-on-interim-review-of-irelands-nitrates-derogation-2019.ph