Investigation of lead exposure as a developmental origin of adult neurodegenerative disease using the zebrafish model system
Abstract
Environmental lead (Pb) exposure is suggested as a developmental origin of adult neurodegenerative diseases such as Alzheimer’s disease (AD). Studies on humans show neurobehavioral or neurodevelopmental alterations in children with a developmental exposure to low levels of Pb. Laboratory animal studies report biological changes related to formation of pathological hallmarks of AD occurring in aged brains of rodents and a non-human primate developmentally exposed to Pb, showing the potential risk of an early life Pb exposure influencing onset of AD. AD research has increasingly applied the zebrafish model system, which has a number of advantages as an in vivo test organism, but there are several AD-related genetic risk factors with limited characterization. The studies in this dissertation first focused on further characterizing known AD genetic risk factors including amyloid precursor protein, presenilins, and apolipoprotein E in adult zebrafish sexing relation to gender. In addition, a newly identified AD-associated gene, sortilin-related receptor, L (DLR class) A repeats-containing was similarly characterized. Next, the influence of an embryonic Pb exposure to 100 μg/L on these AD risk genes was evaluated in brain tissue of each gender. As minimal impacts to these targets were observed, future genome-wide studies at multiple Pb concentrations were conducted to assess additional Pb doses and to further evaluate potential gene expression alterations in adult zebrafish exposed to Pb during embryogenesis. In the transriptome analysis with aged adult zebrafish, we identified that an embryonic exposure to 10 μg/L Pb resulted in female-specific significant expression alterations of genes involved in nervous system development and function and also AD, while these transcriptional changes were not present in males. Likewise, in aged adult females developmentally treated with 100 μg/L Pb, we found significant expression alterations occurring in genes associated with nervous system development and function and neurological disease. On the other hand, there were a number of altered genes related to cancer, tumors, and activation of p38 mitogen-activated protein kinase which was suggested as an upstream regulator involved in biological changes observed in males exposed to 100 μg/L Pb during embryogenesis. Sex-specific comparisons between transcriptome analysis data from zebrafish in the 10 μg/L Pb and 100μg/L Pb studies indicated that an embryonic exposure to different doses of Pb brought about expression changes of unique sets of genes in the aged adult zebrafish. Overall the results of this investigation of both known AD-associated genes and unknown genetic factors addressed the contribution of an embryonic Pb exposure to adult neurodegenerative diseases including AD. These findings show that even a very low level of Pb exposure during embryogenesis can lead to neurological gene expression alterations in later life and suggest that differences in sex of an affected individual and dose of a chemical exposure needs to be considered to determine the latent impacts of a developmental Pb exposure.
Degree
Ph.D.
Advisors
Freeman, Purdue University.
Subject Area
Neurosciences|Genetics|Public health|Environmental science|Surgery
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