Date of Award

12-11-2025

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Biological Sciences

First Advisor

Margaret Whalen

Abstract

Tributyltin (TBT), Dibutyltin (DBT), and Pentachlorophenol (PCP) are persistent environmental contaminants that have been shown to increase immune-cell production of pro-inflammatory cytokines and thus have the capacity to cause chronic inflammation and its associated pathologies such as cancer, cardiovascular disorders, and autoimmune conditions. TBT has been detected in human blood at concentrations up to 260 nM, DBT up to 0.3 µM, and PCP between 0.15 and 5 µM. Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine produced by immune cells in response to pathogen- or damage-associated molecular patterns (PAMPs/DAMPs) via Toll-like receptors (TLRs). Dysregulated TNF-α production contributes to chronic inflammatory pathology. Previous studies have shown that TBT, DBT, and PCP increase pro-inflammatory cytokines through mitogen-activated protein kinase (MAPK) pathways, which function downstream of TLR activation. We investigated whether TBT, DBT, and PCP require TLR1/2 , TLR2, TLR3, TLR4, and TLR8, as well as the adaptor protein MyD88, to stimulate TNF-α production in human peripheral blood mononuclear cells (PBMCs). PBMCs were treated for 1 h with a selective TLR or MyD88 inhibitor, or the corresponding control, prior to 24 h exposure to 25-100 nM TBT, 0.1-0.5 µM DBT, or 1-5 µM PCP. Secreted TNF-α was quantified by ELISA, and cellular levels were determined by Western blot. The results show that inhibition of specific TLRs or MyD88 significantly alters TNF-α production (combination of secreted and cellular levels), with each toxicant displaying distinct receptor dependencies. These findings provide mechanistic insight into how persistent pollutants activate pro-inflammatory cytokine production, potentially contributing to chronic disease.

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