Date of Award

2025-12-01

Degree Name

Doctor of Philosophy

Department

Biosciences

Advisor(s)

Siddhartha Das

Abstract

Prostate cancer (PC) remains the most prevalent malignant disease among the male population worldwide, with a dramatic increase observed in the European Union from the 1980s to the 2000s. The etiology of PC is attributed to both hereditary factors and environmental pollutants. Among these, endocrine disruptors and polystyrene nanoparticles (PSNPs) interact with the prostate gland via the circulatory system, inducing intense oxidative stress. This study aims to characterize, for the first time, the pathobiological effects of PSNPs in both non-malignant (RWPE1) and malignant (22RV1) prostate cell lines. The objective was to elucidate the mechanisms by which environmental pollutants, such as PSNPs, contribute to the initiation and progression of tumors. I hypothesized that small-sized PSNPs, rather than larger particles, dysregulate cancer-related signaling pathways, thereby promoting malignancy in prostate cells. I found that PSNPs ranging from 20 to 1000 nm induced cytotoxicity in both RWPE1 and 22RV1 cells, with RWPE1 cells exhibiting greater susceptibility. PSNPs of 20 and 40 nm were internalized by both cell types and localized to the endoplasmic reticulum, lysosomes, mitochondria, and cytoplasmic compartments. At concentrations of 100 and 200 µg/mL, PSNPs demonstrated intracellular distribution. The predominant form of acute toxicity was non-apoptotic membrane blebbing. Global proteomic analysis revealed significant alterations in the expression of proteins involved in DNA repair, RNA transcription, endosomal and vesicular trafficking, the tricarboxylic acid cycle, and other key metabolic pathways. These changes may underline the induction of malignancy in non-malignant cells and tumor promotion in malignant ones. Notably, components of the ERK/MAPK/P38 and AKT signaling pathways were downregulated, consistent with responses to acute exposure to reactive oxygen species (ROS). Immunoblot analyses using monoclonal antibodies against ERK, MAPK/P38, and AKT support these results. Additionally, significant upregulation was observed in the Hedgehog signaling pathway (GLI1, ZIC2), the RNA polymerase II transcription factor PLRMT, and the promyelocytic leukemia protein (PML), a pattern previously associated with exposure to carcinogens such as arsenic and cadmium, which may constitute the hard corona of PSNPs. This study highlights the potential carcinogenic role of micro- and nano plastics in prostate cancer and underscores the need for further multi-omic and molecular investigations. Importantly, this represents a potentially modifiable environmental factor in prostate cancer pathobiology.

Language

en

Provenance

Received from ProQuest

File Size

99 p.

File Format

application/pdf

Rights Holder

Luis Alfonso Adel-Alvarez

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Biology Commons

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