Year of Award

2020

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Toxicology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Yoon Hee Cho

Commitee Members

Andrij Holian, Curtis W. Noonan, Elizabeth Putnam, Blakely Brown

Keywords

DHA, epigenetic, inflammation, lung, methylation, miRNA

Abstract

Multi-walled carbon nanotubes (MWCNTs) are a class of engineered nanomaterials that pose airborne exposure risks to human health. Immense variations in physical properties such as size and shape complicate understanding the underlying mechanisms and consequences of MWCNT exposures. There are concerns that exposures can lead to chronic pulmonary inflammation and fibrosis diseases, as is the case with other more known ultra-fine respirable materials with similar physical properties, such as crystalline silica and asbestos. Pro-inflammatory diseases can be regulated by epigenetic changes, which can be influenced by environment, including diet. Docosahexaenoic acid (DHA) is an omega-3 fatty acid that may promote resolution of MWCNT- induced inflammation though epigenetic changes, although studies are limited in understanding this process.

In Aim 1 of this project, epigenetic changes in lungs were compared in response to varied MWCNT exposures from a single oropharyngeal dose in adult C57Bl/6 mice to "Narrow Short" (NS), "Wide Short" (WS), or "Narrow Long" (NL). MWCNTs were hypothesized to induce differences in epigenetic changes corresponding to severity in physiological and immunological alterations: DM (Dispersion Media/Control)

Changes in gene-specific methylation corresponded to acute inflammatory responses preceding excessive collagen growth, influenced by MWCNT size/shape properties. Methylation patterns were observed in conjunction with dysregulated miRNA expression which could help position the immune response to variably downregulate inflammation and upregulate tissue remodeling within the acute to sub-chronic interval. After 56d, no differences in airway thickening were observed, which corresponded to the absence of significant differences in gene-specific methylation among MWCNT groups. Collectively, these findings indicate that MWCNT size/shape can influence acute and sub-chronic post-exposure epigenetic alterations corresponding to progression of acute inflammation in lungs.

In Aim 2, to identify potential epigenetic biomarkers of DHA diet modification in response to MWCNT exposure, epigenetic changes were measured using the same methylation and miRNA experimental approaches as in Aim 1. Adult Balb/c mice were fed either a control diet or a 1% DHA-enriched diet before delivery of FA21 (a pro-inflammatory MWCNT) or crystalline silica to determine dysregulated methylation patterns in lungs at 24h (4 weeks of continuous diet) and at 7d post-exposure (5 weeks of continuous diet). miRNA profiling and target predictions were conducted to assess 24h FA21 responses after DHA diet. DHA appeared to offset particle-induced hypomethylation and influenced particle-induced promoter methylation changes 24h and 7d to variable extents. Dysregulated miRNA expression patterns were observed in FA21 exposures and in response to DHA diet. These findings could be beneficial in identifying potential DHA and particle exposure epigenetic biomarkers and could have mechanistic importance in respiratory disease.

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© Copyright 2020 Elizabeth Michelle Cole