Madi, Gulden
(2023)
The impact of long-term vitamin D deficiency on the offspring metabolic health and cognitive function via epigenetic changes.
PhD thesis, University of Nottingham.
Abstract
Exposure to adequate Vitamin D during early development is crucial for neurodevelopment. However, the prevalence of Vitamin D deficiency (VDD) among women of childbearing age is on the rise. This study aims to investigate the impact of maternal VDD on postnatal neurodevelopment and delve into potential underlying mechanisms.
Previous research has linked chronic VDD to an increased risk of metabolic disorders like obesity and diabetes, collectively termed Metabolic Syndrome (MetSyn). To ascertain the relationship between low vitamin D levels and MetSyn, a systematic review and meta-analysis were conducted. The results revealed a negative correlation between low serum vitamin D concentrations and MetSyn, impacting offspring development from pregnancy through adulthood. We then employed an animal model of VDD to measure the molecular impacts of low serum VD concentrations. Female C57BL/6J mice received either a Vitamin D-sufficient (2.2 IU D/g; CD) diet or others a deficient (0.0 IU D/g; VDD) diet for 6 weeks before mating. Their offspring received their respective maternal diet for an additional 8 weeks after weaning, thus, experiencing VDD during both pre-postnatal stages. We assessed the offspring’s metabolic health (changes in whole body physiology and feeding behavior) using the CLAMS method. VDD offspring displayed lower birth weights but experienced increased body weight in adulthood. This weight gain was attributed to reduced oxygen consumption during the dark phase, rather than alterations in food intake or ambulatory activity. In the realm of neurodevelopment, behavioral tests were administered. VDD mice exhibited a significant increase in anxiety-like behavior, though no significant differences in memory and learning were observed compared to the control group. Notably, the effects of VDD seemed to vary based on gender and age, with female 3-week-old female mice and male 8-week-old male mice responding differently.
The VDD mouse model was also used to explore potential links between altered behaviour and neurodevelopment by assessing the rate of cell proliferation and differentiation in the dentate gyrus (DG) and subventricular zone (SVZ). While VDD had no impact on Ki-67 immunoreactivity at either 3-week-old female mice or 8-week-old male mice, it significantly reduced DCX immunoreactivity at 3 weeks. Ki67 immunoreactivity was notably altered in the SVZ at both time points.
Additionally, VDD led to a substantial increase in the expression of KDM6B and UTX, enzymes involved in neurogenesis, in the hippocampus of both 3-week-old female and 8-week-old male VDD offspring. While KDM5A exhibited no significant changes, BDNF expression significantly increased in 8-week-old male VDD mice but not in the 3-week-old female mice. Furthermore, the hypothalamic expression of non-acronymic VGF decreased significantly in both VDD 3-week-old female and 8-week-old male mice, compared to controls.
Experiments were also conducted ex vivo to corroborate the findings. The MTT assay demonstrated that vitamin D significantly influenced cell proliferation, and VD-treated N2a cells exhibited increased axonal projection. NeuroD1 gene expression ASDCEX4RF remained constant across groups, while Syp expression increased on day 1 in VD-treated cells and gradually declined over 3 days.
Collectively, these results indicate that VDD during early development influences adult neurogenesis in the SVZ and DG of the hippocampus. These effects might be modulated by changes in the gene expression of histone (de)methylases, as detailed. Consequently, this study highlights alterations in gene expression pertinent to epigenetic programming within the hippocampus and hypothalamus.
| Item Type: |
Thesis (University of Nottingham only)
(PhD)
|
| Supervisors: |
Toledo, Maria
Jethwa, Preeti |
| Keywords: |
Vitamin D; Neurodevelopment; Neurogenesis; Hippocampus; Hypothalamus; Gene expression |
| Subjects: |
Q Science > QP Physiology |
| Faculties/Schools: |
UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences |
| Item ID: |
76536 |
| Depositing User: |
Madi, Gulden
|
| Date Deposited: |
03 Jun 2025 12:18 |
| Last Modified: |
03 Jun 2025 12:18 |
| URI: |
https://eprints.nottingham.ac.uk/id/eprint/76536 |
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