Author ORCID Identifier
https://orcid.org/0000-0001-7533-3887
Defense Date
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Joseph McClay
Abstract
Exposure to pesticides and other environmental toxins has been associated with persistent neurological and psychiatric dysfunction, but the molecular mechanisms linking prior exposure with long-term changes in central nervous system function remain incompletely understood. The overall objective of this dissertation was to characterize transcriptional and epigenetic dysregulation following toxin exposure in rat models of neurological dysfunction and determine whether persistent epigenetic changes could be pharmacologically modified. First, genome-wide RNA sequencing was used to characterize striatal gene expression following repeated rotenone exposure in a rat model of Parkinson’s disease. RNA sequencing identified 345 differentially expressed genes, including Angpt2, Ddc, and the circadian genes Arntl, Cry1, and Per3, with pathway analysis identifying circadian clock-associated processes. Persistent epigenetic effects of repeated low-dose diisopropyl fluorophosphate (DFP) exposure were subsequently investigated in a rat model of Gulf War Illness. DFP exposure was associated with reduced H3K9 acetylation at Bdnf promoter IV and decreased hippocampal BDNF protein expression months after exposure. A single low dose of ketamine restored H3K9 acetylation and increased BDNF expression toward control levels, demonstrating that persistent epigenetic dysregulation can be modified pharmacologically. Genome-wide hippocampal DNA methylation analysis identified 152 significantly differentially methylated CpGs following DFP exposure despite no significant difference in mean CpG methylation. CpG-associated genes were enriched in neuronal signaling, synaptic organization, glutamate signaling, and calcium transport pathways. Cacna1d-associated CpG was significantly hypomethylated following DFP exposure and inversely associated with increased Cacna1d expression. Finally, age-associated hippocampal methylation was examined in unexposed rats aged 6, 9, 12, and 15 months. Although mean methylation did not differ significantly with age, hundreds of CpGs showed age-associated changes. DFP-associated methylation at Cacna1d overlapped with an age-associated methylation profile. Overall, these findings demonstrate persistent transcriptional and epigenetic dysregulation following toxin exposure and identify potentially druggable pathways associated with long-term CNS dysfunction.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
10-12-2026
Appendix A.1
Appendix A.2.xlsx (18 kB)
Appendix A.2
Appendix A.3.csv (3 kB)
Appendix A.3
Appendix A.4.xlsx (21 kB)
Appendix A.4
Appendix A.5.xlsx (320 kB)
Appendix A.5
Included in
Environmental Health Commons, Genomics Commons, Molecular and Cellular Neuroscience Commons