Al-Mousa, Fawaz Ali F (2011)
Ph.D. thesis, University of Birmingham.
Restricted to Repository staff only until 01 July 2015.
Brominated flame retardants (BFRs) and alkylphenols (APs) are pollutants commonly found within the environment and have human health concerns due to their endocrine disrupting and cytotoxic effects. BFRs are used to reduce the flammability of a variety of consumer products such as foam furnishings, whereas APs are found in plastic products used by the food industry. This study investigated the neurotoxicity of the most commonly used groups of BFRs and APs on SH-SY5Y human neuroblastoma cells. The results presented in this thesis showed (using cell viability assays) that these pollutants are toxic at low concentrations. Some compounds such as hexabromocyclododecane (HBCD) and 4-nonylphenol (4-NP) induce cell death (apoptosis) by caspases activation (Casp-8, Casp-9 and Casp-3) and cytochrome c release at low micromolar concentrations (IC50 ~ 4μM and 6μM, respectively). Consequently this study also showed that these compounds increased intracellular [Ca2+] levels and the production of reactive oxygen species (ROS) within SH-SY5Y cells by causing Ca2+-dependent depolarization of the mitochondria. In support of a Ca2+-mediated mechanism, the data presented here shows that some BFRs and APs inhibit Sarcoplasmic/ Endoplasmic Ca2+-ATPase (SERCA) and to corroborate this over-expressing SERCA1 improved cell viability especially in cells exposed to certain cytotoxic chemicals such as HBCD; this study is the first experiment of this type to be performed. This study also showed that some of these chemicals, at low concentrations had amyloidgenic effects causing the cleavage amyloid precursor protein (APP) into Beta-amyloid (Aβ) and could therefore be implicated in Alzheimer‟s disease (AD).
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