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The Effect of Early Life Aflatoxin Exposure on Growth, Immune

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The Effect of Early Life Aflatoxin Exposure on Growth, Immune The effect of early life aflatoxin exposure on growth, immune function and cancer predisposition Jovita Marie Castelino Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Medicine September 2013 I confirm that the work submitted is my own and that appropriate credit has been given where reference has been made to the work of others This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement © 2013 “The University of Leeds and Jovita Marie Castelino” Acknowledgements I am very grateful for the supervision, advice and support I received from my supervisors, Drs. Yun Yun Gong and Michael Routledge. I would also like to thank Professor Chris Wild and the International Agency for Research on Cancer for funding this research project. This work would not have been realised without collaboration with Shona Wilson and David Dunne from the Schistosomiasis Research Group, University of Cambridge; Branwen Hennig, Sophie Moore, Paula Dominguez-Salas, Andy Hall and Andrew Prentice from the London School of Hygiene and Tropical Medicine; and Zdenko Herceg and Hector Hernandez from the Epigenetics Group, IARC. I would also like to thank Marie Pierre Cros, Geoffroy Durand, Cyrille Cuenin, Ho- Sun Lee and Akram Ghantous for their advice and help with the whole genome work. Additionally, I would like to thank Yu-Kang Tu for his advice on the statistical analysis in Chapter 3. I am indebted to the contributions and invaluable advice from Hector Hernandez in the execution of the whole genome work and the preparation of the relevant sections in this thesis. Importantly, this work would not have been possible without the participants from Kenya and The Gambia. I would like to thank Anna Skromna, Victoria Richardson, Kay White, Anne Sutcliffe, Susan Shires, Catherine Whibley, André Nogueira Da Costa, Claire Smith, Qizhi Huang, John Huntriss, Angela Carter, Jill Callaghan, Chou Srey, Xiaoxi Pan, Nikoletta Pechlivani, Jon Askham, Bin Zhao, Jianping Lu, Matt Gage and Tim Noble, who have helped me during my time at LIGHT. I am very grateful and blessed to have had scientific and emotional support, advice and positive encouragement from my husband, Matthew Cotterill. I thank him for being with me every step of the way and allowing me to grow as a person. The emotional support and love from my wonderful parents, my beautiful and strong sisters, my ever-helpful in-laws and Mojo has also been vital throughout my PhD and I am forever indebted to them. iii Abstract Aflatoxin exposure through contamination of dietary staples is prevalent in developing regions such as sub-Saharan Africa. Aflatoxin exposure has been linked to a GT transversion in p53, which has been suggested to be the main mechanism of aflatoxin-associated liver carcinogenesis. In young children, in utero and weaning exposure has been linked to growth and immune function impairment through unknown mechanisms. The role of the insulin-like growth factor (IGF) axis was examined in aflatoxin-exposed Kenyan school-children. Through analysis of plasma samples, it was identified that 16% of the effect of aflatoxin on growth impairment was through disrupted IGF1 levels. It was also observed that mRNA and secreted protein levels of IGF growth-axis components were significantly reduced in aflatoxin-treated cultured liver cells. In another study using a Gambian mother-child cohort, it was determined that in most women aflatoxin exposure was consistently high or low during gestation and that this exposure was influenced by season of exposure. In infants born to highly aflatoxin-exposed women, significant changes to DNA methylation and gene expression patterns in white blood cells were observed in a number of genes following whole genome analysis. Among the observed changes, hypomethylation of HORMAD2 at the promoter-level and MIR24-2 at the gene-level as well as hypermethylation of CD3D at the promoter-level were identified and successfully validated by pyrosequencing. Additionally, USP4 and STAT3, associated with cancers and growth impairment, were both upregulated in the high AFB1 exposure group and were also successfully validated by qPCR. Changes in methylation and expression in aflatoxin-treated liver cells were assessed using a iv whole genome approach. Hypomethylation of IL2 and MIR24-2 at the gene level and upregulation of NFKB1A and IL6 were observed in AFB1-treated liver cells compared to controls. Overall, the study provides evidence that the IGF axis may be involved in aflatoxin-induced growth impairment and the STAT3 and NF-κB signalling pathways, associated with hepatocarcinogenesis and growth impairment, were found to be activated in both Gambian infants exposed in utero and in treated liver cells. These pathways may play important roles in the mechanisms of aflatoxin exposure-associated health effects and need to be explored further. v Table of Contents Acknowledgements ............................................................................................................... iii Abstract .................................................................................................................................. iv Table of Contents .................................................................................................................. vi List of Tables ......................................................................................................................... xi List of Figures ...................................................................................................................... xiv Abbreviations ...................................................................................................................... xvi 1 Introduction ..................................................................................................... 1 1.1 Literature Review ...................................................................................... 2 1.1.1 Discovery of Aflatoxins ............................................................................... 2 1.1.2 Contamination of crops with aflatoxin ......................................................... 4 1.1.3 Impact of aflatoxins on animal and human health ....................................... 6 1.1.3.1 Structure of AFB1 related to health effects .............................................. 6 1.1.3.2 Metabolism of AFB1 ................................................................................ 9 1.1.4 A brief history of the effects of AFB1 on the human liver ......................... 13 1.1.4.1 Evidence of a potential mechanism of AFB1-associated cancer ............ 15 1.1.4.2 Hepatitis B virus, aflatoxins and liver cancer ........................................ 17 1.1.5 Advantages of biomarkers ......................................................................... 18 1.1.6 Molecular markers of AFB1 exposure ........................................................ 19 1.1.6.1 Methods of AF-alb measurement ........................................................... 22 1.1.7 Aflatoxin exposure levels and associated health effects ............................ 24 1.1.7.1 AFB1 exposure and liver cancer risk ...................................................... 24 1.1.7.2 Epigenetics: Role in cancer prediction, diagnosis and prognosis .......... 30 1.1.7.3 Identifying mechanistic markers of gene expression and epigenetic alterations ............................................................................................................... 35 1.1.8 Child growth and development .................................................................. 38 1.1.9 AFB1 exposure and effects on growth ....................................................... 40 1.1.9.1 Mechanisms of growth impairment ....................................................... 44 1.1.9.2 Role of epigenetic modifications in growth ........................................... 50 1.1.10 The foetal origins of adult disease ............................................................. 51 1.2 Project Aims ............................................................................................ 56 2 Materials and Methods ................................................................................. 57 vi 2.1 AF-alb measurement ELISA ................................................................... 58 2.1.1 Modified AF-alb measurement ELISA ...................................................... 61 2.2 IGF1 and IGFBP3 ELISA measurement ................................................. 62 2.2.1 Plasma samples .......................................................................................... 62 2.2.2 Cell media samples .................................................................................... 63 2.3 Non-tumourigenic cell work .................................................................... 64 2.3.1 Cell maintenance ........................................................................................ 64 2.3.2 Cell cytotoxicity assay ............................................................................... 64 2.3.3 Cell treatment with AFB1 ........................................................................... 65 2.3.4 DNA extraction .......................................................................................... 66 2.3.5 RNA extraction .........................................................................................
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