The effect of micronutrients in oxidative stress, proliferation and apoptosis in placenta

Abstract

This thesis is comprised of seven chapters: a general thesis introduction (Chapter 1), one Published review of the literature (Chapter 2), one published research article (Chapter 3), one submitted research article (Chapters 4), one unpublished research chapter written in manuscript style (Chapters 5), a published systematic review (Chapter 6), and a final general discussion (Chapter 7). Chapter 2 is a published comprehensive review of the impact of maternal selenium and iodine on placental and child health (Habibi et al., Nutrients 2020). A few studies showed that selenium could increase antioxidant enzyme activity in placental cell lines. Additionally, population studies revealed that selenium and iodine deficiency separately were associated with a greater risk of pregnancy complications. However, there are no studies that have investigated the potential synergistic effect of iodine and selenium combined on placental health. To address this gap in the literature, the role of these two essential micronutrients during pregnancy and in relation to oxidative stress has been comprehensively reviewed. This review supports the hypothesis that selenium and iodine could potentially have a synergistic role in protecting against oxidative stress in the placenta. We went on to test this hypothesis in Chapters 3 and 4. Chapter 3 is a published original research study describing the effect of iodine and selenium on proliferation, viability, and oxidative stress in HTR-8/SVneo placental cells (Habibi et al., Biological Trace Element Research 2020). Our study showed that oxidative stress reduces HTR-8/SVneo cells viability and increases lipid peroxidation, which is oxidative damage to the cell membrane. Interestingly, selenium and iodine supplementation separately or together could protect cells against oxidative stress. A supraphysiological concentration of selenium caused some toxic effects in cells that were not exposed to oxidative stress. Interestingly, the same concentration in cells treated with oxidative stress was protective suggesting a higher demand of selenium in HTR-8/SVneo placental cells to combat oxidative stress. The combination of selenium and iodine provided a greater protection against oxidative stress to the cells compared to their individual supplementation suggesting a synergistic effect in HTR-8/SVneo placental cells. Chapter 4 is original research describing how selenium and iodine can protect first trimester human placenta against oxidative stress and what the effect of copper is in the placenta (submitted to Human Reproduction on 19th August 2020). For the first time, using laser ablation inductively coupled plasma-mass spectrometry, we showed the selenium and copper distribution in the treated human first trimester placenta explants. We investigated the potential mechanism of the effect of iodine, selenium and copper on first trimester human placenta. Oxidative stress increased DNA damage and apoptosis and supplementation with iodine or selenium was protective resulting in reduced DNA damage and apoptosis in first trimester placenta explants. Supplementation with a combination of iodine and selenium provided a greater reduction in oxidative damage to DNA molecules suggesting a synergistic effect against oxidative stress in the placenta. A high concentration of copper increased DNA damage and apoptosis in the placenta in the absence of induced oxidative stress. However, this was not seen when placenta tissue explants were exposed to oxidative stress suggesting a higher consumption of copper during oxidative stress. Chapter 5 is an unpublished original manuscript describing associations between buffy coat mitochondrial DNA content and maternal micronutrient status and pregnancy outcome (To be submitted to the International Journal of Molecular Sciences). Using 317 samples of participants of Screening for Pregnancy Endpoints (SCOPE) study in Adelaide we investigated the association between maternal mitochondrial DNA content at 15 ± 1 weeks’ gestation with micronutrient status and pregnancy outcomes. We found that higher inflammation, defined by increased C-reactive protein concentration, was associated with reduced mitochondrial DNA content. A lower mitochondrial DNA content at 15 ± 1 weeks’ gestation was associated with a greater risk of pregnancy complications. There was no association between mitochondrial DNA content and micronutrient status. Mitochondrial DNA content may reflect risk of pregnancy complications but it is not a strong predictor and it was not associated with maternal micronutrient status. Chapter 6 is a published systematic review on maternal diet and offspring telomere length (Habibi et al., Nutrition Reviews 2020). Maternal nutrition may be an important determinant of offspring telomere length that is a biomarker of ageing and chronic diseases. Therefore, we systematically reviewed all available literature about the association of maternal nutrition and offspring telomere length. We found little evidence on such an essential topic. However, there were seven studies on this topic and collectively they showed that higher maternal circulating folate and 25(OH)D3 and dietary caffeine intake, were associated with longer offspring telomere length, whereas dietary intake of carbohydrate, folate, n-3 PUFA, vitamin C or sodium, was not. This systematic review highlighted the necessity for further research in this area. Chapter 7 is the final chapter that presents a summary of my PhD work and general discussion of all findings of this project and suggests future research directions.