Abstract
Endocrine disrupting chemicals (EDCs) are exogenous compounds that can alter normal hormone production, signaling, and function(s), potentially leading to adverse effects on human health and the environment. Exposure during critical windows of development can lead to long-term health effects on an individual and subsequent generations. Therefore, this thesis aims to evaluate the impact of EDCs exposure at various levels of complexity such as effects on cellular health, receptor function, organ development and function, and human health effects. Various in vitro, in silico and quantitative methods have been utilized for the assessment of mixture effects of EDCs. It also highlights the use of quantitative structure-activity relationship (QSAR) models to predict chemicals based on their structural properties that can potentially disrupt the hormonal systems.Overall, this thesis shows that the EDC exposure at cellular level can affect subtle markers of cellular health such as mitochondrial membrane potential, indicating an altered mitochondrial metabolism. At receptor level, the mixture effects of the POPs on estrogen and progesterone receptors are observed. Exposure to POP mixture led to an increased agonistic/ synergistic response in the estrogen responsive MMV-Luc cells and significant antagonist response in progesterone responsive TM-Luc cells. At organ level, EDCs exposure is shown to affect the neuronal connectivity via NGF-induced neurite outgrowth. The early prioritisation of EDCs via the use of alternative in silico methods in combination with in vitro techniques is also assessed. A good correlation between in silico predictions and in vitro bioassays demonstrated the importance of using alternative methods for early prioritisation of EDCs. At human level, the early life exposure to EDCs via breast milk is shown to interact with the GLP-1R gut hormone receptor, leading to the impairment of normal GLP-1R function.
Thesis is embargoed until 31 July 2026.
| Date of Award | Jul 2023 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Sponsors | EC/Horizon 2020 Marie Skłodowska-Curie actions |
| Supervisor | Lisa Connolly (Supervisor), Steven Verhaegen (Supervisor), Erik Ropstad (Supervisor) & Brian Green (Supervisor) |
Keywords
- Endocrine disrupting chemicals
- persistent organic pollutants
- pre-lethal cytotoxicity
- hormone receptors
- neuritogenesis
- human milk extracts
- mycotoxins
- high content analysis
- GLP-1 receptor signalling
- reporter gene assays
- estrogen
- progesterone
- live imaging
- mass spectrometry
- QSAR
- predictive toxicology