Date on Master's Thesis/Doctoral Dissertation

12-2025

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

O'Toole, Timothy E.

Committee Member

Haberzettl, Petra

Committee Member

Srivastava, Sanjay

Committee Member

Hein, David

Committee Member

Moore IV, Joseph

Author's Keywords

particulate matter 2.5; aging; telomeres; cell senescence; endothelial activation; senolytics; telomerase activity

Abstract

Inhalation of fine airborne particulate matter (PM2.5) is an environmental risk factor for numerous health disorders, including cardiovascular diseases (CVD). While several studies have shown that PM2.5 exposure can induce oxidative stress, DNA damage, and inflammation, the underlying mechanisms that translate these effects into systemic pathology remain poorly understood. Some recent studies have shown that PM2.5 exposure can lead to telomere shortening in leukocytes, but the generality of this outcome and contribution to endothelial dysfunction has not yet been fully explored. We hypothesized that PM2.5inhalation accelerates cellular aging and senescence in both circulating peripheral blood mononuclear cells (PBMNCs) and endothelial progenitor cells (EPCs), thereby promoting endothelial activation and increasing susceptibility to CVD. To assess this, 12-week-old male C57BL/6J mice were exposed to concentrated ambient fine particles (CAPs) or filtered air for 6 h/day for 9 consecutive days. Additionally, to test whether carnosine protects against the impact of CAPs on stem cell aging, mice were treated with carnosine (dose, route etc.). After euthanasia, PBMNCs were isolated and EPCs were cultured. Telomere length was assessed using an established PCR method while cellular senescence was assessed by flow cytometry measuring β-galactosidase activity or the expression of characteristic senescence-associated genes by Real time PCR. Our results showed that CAPs exposure led to telomere attrition and increased senescence in both PBMNCs and EPCs. The telomere shortening effects were accompanied by impaired activity of telomerase reverse transcriptase indicating its possible mechanistical link. The effect of CAPs on telomere attrition and cellular senescence was reduced in mice that received the dipeptide carnosine. To assess in vivo functional consequences of senescence, i.e. endothelial activation, we quantified leukocyte rolling and adhesion in mouse ear vasculature using multiphoton intravital microscopy. We observed that CAPs-exposed mice had increased numbers of these cells. This effect was mitigated in CAPs-exposed mice that received the senolytic compounds Dasatinib and Quercetin (DQ) which eliminate senescent cells selectively. In conclusion, exposure to CAPs promoted telomere attrition and cellular senescence in PBMNCs and EPCs, contributing to endothelial dysfunction. These outcomes may contribute to the widespread tissue toxicity of PM exposure and intervening in these processes may limit adverse outcomes (carnosine, senolytics).

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