Degree

Doctor of Philosophy (PhD)

Department

Physics

Document Type

Dissertation

Abstract

Current radiobiological models focus primarily on nuclear DNA damage and fail to fully explain radiation-induced noncancerous health effects. This dissertation investigates whether non-nuclear subcellular structures contribute to radiation-induced biological damage through experimental biomarker analysis and computational microdosimetry. The central hypothesis posits that whole-body photon irradiation results in subcellular non-nuclear damage, specifically increased circulating mitochondrial DNA concentrations, that correlates with radiation dose and long-term noncancerous effects such as cardiovascular disease.

Specific Aim 1 measured mitochondrial and nuclear DNA concentrations in banked blood samples from 72 Chinese rhesus macaques that previously received whole-body photon irradiation ($0-10$ Gy) from Cobalt-60 or LINAC sources. Using quantitative polymerase chain reaction, cell-free DNA concentrations were analyzed at two timepoints and correlated with irradiation history and medical observations. While conventional statistical analysis did not demonstrate significant dose-response relationships, exploratory analysis revealed suggestive associations between mitochondrial DNA levels and both radiation exposure and cardiovascular health issues. A significant positive correlation ($\rho = 0.393$) was observed between nuclear and mitochondrial DNA concentration changes, suggesting coordinated cellular damage mechanisms.

Specific Aim 2 developed a simplified computational cardiac myocyte model for 3D Monte Carlo transport calculations using PHITS. The model incorporated key organelles with realistic chemical compositions. Simulations with 10 million primary photons revealed that secondary electrons constituted the primary energy deposition mechanism. Critically, smaller organelles like the inner mitochondrial matrix and endoplasmic reticulum demonstrated significantly higher energy deposition density per unit volume compared to larger structures, with 28 of 52 energy-depositing electrons producing statistically significant biological damage events.

The integration of experimental and computational approaches supports the hypothesis that mitochondrial and endoplasmic reticulum dysfunction contributes meaningfully to radiation-induced cellular damage beyond nuclear DNA injury. These findings challenge conventional radiobiological frameworks and demonstrate that significant subcellular dysfunction may occur even when nuclear DNA damage is not immediately lethal, potentially contributing to delayed cardiovascular pathology. This work has important implications for radiation protection, radiotherapy treatment planning, and understanding dose-response relationships for noncancerous late effects in occupational and clinical radiation exposure scenarios.

Date

7-11-2025

Committee Chair

Schneider, Chris

DOI

10.31390/gradschool_dissertations.6885

Download

Share

COinS