|dc.description.abstract||Pregnancy is a physiologically demanding process, vulnerable to several modifiable lifestyle factors including diet. Malnutrition, or a dietary imbalance, can have severe implications on maternal physiology, as well as placental and fetal development. Several aberrant pregnancy outcomes have been linked with an abnormal diet disturbing maternal metabolism, hormone status and placental function. Dietary changes also disrupt the intrauterine environment for the developing fetus, altering growth and predisposing offspring to development of diseases later in life. Abnormal pregnancy outcomes are dependent on the specific timing and type of dietary insult. A major micronutrient deficiency present in multiple human populations is selenium. Deficiencies in micronutrients, such as selenium, have been linked to numerous pregnancy complications; however, the specific ramifications of a selenium deficient diet on pregnancy outcomes and fetal development is relatively unknown. Selenium is incorporated into selenoproteins involved in numerous biological and cellular processes including antioxidant function, thyroid hormone metabolism, endoplasmic reticulum stress and skeletal muscle development. Given selenium is associated with undesirable pregnancy outcomes, the primary aim of this thesis was to investigate the effects of selenium deficiency on pregnancy physiology, placental function, fetal development and offspring outcomes.
Chapter 3 explored the effects of a maternal selenium deficit on gestational physiology, placental development and function, as well as fetal development. Although selenium deficiency is common, the specific ramifications of a selenium deficit on pregnancy is poorly understood. Female C57BL/6 mice were randomly allocated to either a control (>190 μg kg-1) or selenium deficient diet (<50 μg kg-1); mice were subjected to their respective diets four weeks prior to mating and throughout gestation. Data illustrated that an isolated maternal selenium deficit reduced maternal weight gain during gestation and fetal growth. Furthermore, thyroid hormone levels were increased in both maternal and fetal plasma, concomitant to a reduction in iodothyronine deiodinase expression within the placenta. Fetal blood glucose levels were also reduced, which was associated with an increase in placental glycogen content and an increase in placental GLUT3 expression. Although there were no changes to placental development, gene expression of several nutrient transporters, selenoproteins and antioxidant response genes were altered. These pregnancy outcomes likely preceded programmed disease outcomes in later life, which prompted further study in offspring models.
The effect of exposure to selenium deficiency in utero during fetal development was explored in Chapters 4 and 5. The offspring model in Chapter 4 indicated that exposure to a selenium deficit during development may induce peripheral insulin resistance in offspring in a sex specific manner. Both male and female offspring exhibited glucose intolerance and altered thyroid hormone levels. Furthermore, Chapter 5 showed that voluntary exercise was reduced by selenium deficiency and subsequently the programmed glucose intolerance was not alleviated. These studies both reiterated the importance of adequate selenium intake during pregnancy for offspring metabolic health.
Chapter 6 characterised the expression of fourteen key selenoproteins in maternal, fetal and offspring tissues, and how this was impacted by perinatal and antenatal selenium deficiency. The gene expression of these selenoproteins was determined in the liver, kidneys and heart of all animals, as well as the placenta. A selenium deficit caused a reduction in several selenoproteins in all maternal tissues investigated, as well as the placenta. Intriguingly, expression of several selenoproteins within the liver, kidneys and heart of male and female fetuses was significantly increased. As offspring were placed on normal selenium diets after weaning, only slight changes in selenoprotein expression were observed in offspring; however, a sexually dimorphic relationship in selenoprotein expression was evident. This was the first study to demonstrate that transcriptional regulation of selenoproteins is complex and multifaceted, with expression exhibiting tissue-, age- and sex-specificities. This study also emphasized the importance of dietary selenium in maintaining the selenotranscriptome, and that deficiency of selenium during pregnancy has genomic programming potential.
Finally, Chapter 7 explored the relationship between different serum selenium levels during pregnancy and thyroid function. This study indicated that the selenium status of pregnant women in South East Queensland may not be satisfactory. Additionally, this clinical study associated reduced serum selenium during pregnancy with reduced free triiodothyronine (fT3) levels, increased thyroid peroxidase antibodies (TPOAb), increased free thyroxine/thyroid stimulating hormone (fT4/TSH) ratio and an increased incidence in pregnancy complications, most notably GDM.
Overall, this doctoral thesis has identified thyroid and metabolic specific outcomes following maternal exposure to a selenium deficit during pregnancy, which may contribute to pregnancy complications and programming of metabolic disease. These results highlight that dysregulation of individual micronutrients, such as selenium, can have significant long-lasting ramifications on reproductive outcomes. Therefore, atypical levels of micronutrients in pregnant women should be considered as a significant risk.||