- Title
- Increased oxidative damage and premature placental aging contribute to the aetiology of stillbirth
- Creator
- Sultana, Zakia
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2018
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Stillbirth is a neglected public health problem affecting more than two million women and families globally each year with devastating and long-lasting psychosocial and financial impact. Rates of stillbirth, even in high-income countries with access to optimal obstetric care, have remained static in the past two decades. The causes of, or associations with, stillbirth that have been identified clinically include fetal factors such as genetic/structural abnormalities and growth restriction, maternal factors such as preeclampsia and infections and placental factors such as abruption and placenta previa. However, no specific cause has been established for the majority of stillbirths at term, and the rate of this category of death rises drammatically as gestation progresses beyond 38 weeks. Taking into account the functional definition of aging that is an increase in the risk of death with time, and the existence of placental pathologies in the unexplained stillbirth pregnancies resembling aging in other organs, we hypothesise that premature placental aging may be the primary factor in the aetiology of unexplained stillbirth. Premature aging may occur when cells experience increased oxidative stress that causes damage to cellular macromolecules, including DNA, RNA and lipids, and alters protein expression patterns, especially those that are crucial for cellular survival and function. Therefore, the primary aim of this thesis was to investigate evidence that the placenta from late-gestation shows biochemical signs of oxidative damage and aging that would also be present in placentas associated with stillbirths. A further aim was to investigate the pathways that mediate the oxidative damage and aging in the placenta in pathologic pregnancies. We have shown that placentas from both late-term and stillbirth pregnancies show biochemical signs of aging in the form of increased DNA and lipid oxidation. Also, the expression of aldehyde oxidase 1 (AOX1), which is known to be involved in reactive oxygen species (ROS) generation and oxidative stress, is increased in placental tissues obtained from both late-gestation and stillbirth pregnancies. We tested the association of AOX1 in stillbirth pregnancy as an RNA sequencing study performed in our laboratory identified a significant increase in AOX1 mRNA in late-term placentas compared to term healthy placentas (unpublished). The demonstration of G-protein coupled estrogen receptor 1 (GPER1), a cell surface estrogen receptor, localisation on the apical surface of the normal placental syncytiotrophoblast and its role in the reduction of ROS generation and oxidative damage indicate that this receptor may be a critical step in the pathway of placental ROS induced oxidative damage. Using a placental explant and a cell line culture model, we then tested the pathways that regulate placental oxidative damage and aging. Results presented in this thesis revealed that growth factor removal resulted in placental oxidative damage, with impaired mitochondrial function, decreased expression of sirtuins (proteins that control aging), alteration of nutrient sensing mammalianTORC1, and energy sensing AMP activated protein kinase pathways, all the changes are known to be associated with oxidative damage and aging in other tissues. Inhibition of AOX1 or stimulation of estrogen activation at GPER1 resulted in the blocking of all the changes observed after removal of growth factors. Together, these findings support the hypothesis that placental oxidation is regulated by estrogen activation at the GPER1 and inhibition of AOX1 leading to the inhibition of ROS generation and oxidative stress. Our study identifies potential biomarkers of oxidative damage and aging in stillbirth placentas that raise the possibility that these biomarkers of placental oxidative damage and aging may be released into the maternal blood where they may have diagnostic value in predicting the fetus at risk for stillbirth. Treatment targeting AOX1 and/or GPER1 may arrest the oxidative damage in the placenta in pregnancies identified at risk and may lead to novel therapeutic strategies for delaying placental aging, as well as preventing stillbirth and other age-related adverse pregnancy outcomes.
- Subject
- stillbirth; placenta; DNA oxidation; thesis by publication; placental aging; oxidative stress; fetal death; lipid peroxidation; aldehyde oxidase 1; G protein-coupled estrogen receptor 1; 4-hydroxynonenal; mitochondrial function
- Identifier
- http://hdl.handle.net/1959.13/1391445
- Identifier
- uon:33234
- Rights
- Copyright 2018 Zakia Sultana
- Language
- eng
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 14 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 499 KB | Adobe Acrobat PDF | View Details Download |