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Title: The effect of early life aflatoxin exposure on growth, immune function and cancer predisposition
Author: Castelino, Jovita Marie
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2013
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Aflatoxin exposure through contamination of dietary staples is prevalent in developing regions such as sub-Saharan Africa. Aflatoxin exposure has been linked to a G→T 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 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.
Supervisor: Gong, Yun Yun ; Routledge, Michael Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available