Latent Effects of Exposure to Lead and the Association with Neurological Outcomes via Epigenetics and Genetics

Gene-environment interaction;Epigenetics;Lead exposure;Pb exposure;Cognitive decline;Neurosciences;Public Health;Health Sciences;Environmental Health Sci PhD

Farooqui, ZishaanPaulson, Henry L ;

University of Michigan

关键词: Gene-environment interaction;    Epigenetics;    Lead exposure;    Pb exposure;    Cognitive decline;    Neurosciences;    Public Health;    Health Sciences;    Environmental Health Sci PhD;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/137078/zafa_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Cognitive function is measured on a spectrum that ranges from normal cognition to severe dementia. The environment may interact with genes to influence susceptibility to cognitive decline via interaction with single nucleotide polymorphisms (SNPs) or by modification of the epigenome. The aim of this thesis is to examine how genetics and epigenetics interact with Pb to influence cognitive decline.We first characterize the association between cumulative Pb exposure and longitudinal changes in scores on the mini-mental status exam (MMSE) in men in the Normative Aging Study (NAS). Using longitudinal modeling, we find that an increase in Pb is associated with a lower baseline MMSE and a faster decline in the rate of MMSE. We also report that an increase in patella Pb may confer added risk of cognitive impairment, which we define as MMSE score dropping below 25.Next, we investigate whether SNPs found to be associated with AD in genome-wide association studies modify the association between Pb and the risk of cognitive impairment. We find that an IQR increase in patella Pb does not confer a change in risk of impairment for subjects who were homozygous for the major allele at the CR1 and PICALM genes. However, for carriers of the variant allele at CR1 and PICALM, there was an increased risk of cognitive impairment over the observation period.Finally, we test the hypothesis that DNA methylation is modified by in utero exposure to Pb in a mouse model. Offspring were exposed to Pb in utero via maternal drinking water. We probed DNA methylation levels in a neuron-specific cell population at a genome-wide level. Mice exposed in utero to 32 ppm Pb have 7554 (65.6% of differentially methylated probes) probes that are hypomethylated and 3963 (34.4%) that are hypermethylated. We also report exposure-dependent, differentially methylated regions in histamine N-methyltransferase (Hnmt) and protocadherin 19 (Pcdh19).This thesis illustrates that prior exposure to Pb modulates cognition via interaction with genetic variants and the epigenome. This paves the way for understanding how environmental exposures exert latent effects over the lifetime of an organism vis-à-vis their interaction with the genome.