Author ORCID Identifier
Semester
Summer
Date of Graduation
2024
Document Type
Dissertation
Degree Type
PhD
College
School of Public Health
Department
Occupational & Environmental Health Sciences
Committee Chair
Travis Knuckles
Committee Co-Chair
Michael McCawley
Committee Member
Christa Lilly
Committee Member
Justin Hettick
Abstract
Exploring the routes of exposure and biological fate of 4,4’-methylene diphenyl diisocyanate (MDI) has been a challenge for many years. Occupational exposure to MDI can result in the development of occupational asthma (MDI-OA) which results in loss of productivity, large economic costs, and costs to the individual worker. Initially, it was thought that respiratory exposure to MDI was the most likely route leading to MDI-OA. Industries utilizing MDI have been successful at controlling airborne concentrations according to industrial hygiene assessment and newly diagnosed cases of MDI-OA decreased and plateaued. New research suggests that dermal exposures to MDI may explain this plateau. Medical diagnosis of MDI-OA is also challenging since the majority of those diagnosed have no specific IgE to MDI even though the disease has many hallmarks of allergic asthma. The collection of studies presented here were intended to use a discovery approach in the spirit of multi-omics to take a broad biological view of a simulated dermal exposure using primary human epidermal keratinocytes exposed to MDI conjugated to reduced glutathione (GSH), an important antioxidant found in almost every tissue including the epidermis. The conjugation reaction of MDI and GSH has been shown by other researchers to form a more stable chemical entity at physiologic temperatures and pH. Utilizing gene expression, proteomics, and metabolomics the goal of this study was to find gene expression, proteins, and metabolites that could offer insight on pathways that could be involved downstream of a dermal exposure to MDI. This study provided evidence that keratinocytes (the predominant cell in the epidermis) have the capacity to react to MDI exposure. These studies revealed evidence of the activation of innate immune system pathways in the form of gene expression data, label-free quantitative proteomic data, and metabolomic data. Evidence included increased gene expression related to cytokines, chemokines, alarmins including IL1B, TSLP, and IL33. Specifically, TSLP and IL33 are important alarmins that can lead to the activation of innate lymphoid cells type II, a cell that has been shown to play an important role in allergy and asthma. Proteomic data showing an increased expression of the proteins S100A8 and S100A9, important innate immune alarmins and endogenous ligands for receptors for advanced glycation end-products and toll-like receptors. Finally, metabolomics data supported evidence that immune pathways can be activated. When this data is merged into a holistic dataset there is strong evidence that innate pathways may be activated after exposure to MDI-GSH conjugates and that the dermal route of exposure may activate immune pathways. Taken as a whole, these studies show that this type of approach has the potential to shed light on challenging research problems when more targeted approaches have struggled to find answers.
Recommended Citation
Law, Brandon F., "Characterizing 4,4’-Methylene Diphenyl Diisocyanate Exposure in Primary Human Epidermal Keratinocytes: A Multi-Omics Approach" (2024). Graduate Theses, Dissertations, and Problem Reports. 12539.
https://researchrepository.wvu.edu/etd/12539
Embargo Reason
Publication Pending
Included in
Bioinformatics Commons, Molecular Biology Commons, Occupational Health and Industrial Hygiene Commons
Comments
Requesting a 1-year embargo.