Date of Award

8-28-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Information Science

First Advisor

Antiño Allen

Abstract

Acute Lymphoblastic Leukemia (ALL) is a hematologic malignancy that primarily affects children and young adults. While advancements in treatment—including chemotherapy and cranial irradiation—have significantly improved 5-year survival rates in children to nearly 90%, radiation-induced cognitive impairment (RICI) remains a persistent and debilitating side effect. The brain, particularly the hippocampus, is highly susceptible to radiation-induced oxidative stress and inflammation. In the treatment of ALL, the combined use of chemotherapy and radiotherapy contributes to a heightened oxidative burden, exacerbating the risk of cognitive dysfunction. Although previous studies have linked radiation exposure to neurocognitive decline, the molecular mechanisms underlying RICI and chemotherapy-induced cognitive impairment remain poorly defined. As a result, there is a growing need to develop effective strategies to prevent or mitigate these complications. Emerging evidence points to sulforaphane (SFN)—a dietary antioxidant compound known to activate the Nrf2 pathway and reduce reactive oxygen species (ROS)—as a promising neuroprotective agent. While SFN’s protective role has been documented in various models of neurological damage, its specific impact on chemotherapy-induced cognitive impairment in the context of ALL treatment remains underexplored. In this study, using a mouse model (C57Bl/6 male mice) we employed a multi-omics approach to investigate SFN’s potential to mitigate cognitive, intestinal, and gut microbiota disturbances induced by a Vincristine–Methotrexate–Leucovorin chemotherapy regimen in male mice. Additionally, we examined the effects of cranial 10 Gy radiation on cognition and assessed SFN’s capacity to alleviate radiation-induced cognitive deficits. We hypothesized that SFN would mitigate cognitive impairments. Our integrated transcriptomic and proteomic analyses following radiation exposure revealed a widespread disruption in neuronal signaling, synaptic function, mitochondrial dysfunction and inflammatory pathways. Molecular targets such as CREB and PSEN1 were also identified as key central molecules which may be considered for potential therapeutic interventions aimed at mitigating RICI. Our findings indicate that SFN exerts clear neuroprotective effects under radiation exposure, with improvements observed at behavioral, transcriptional, and histological levels. This was marked by significant improvements memory and restoration of hippocampal neuronal density. In contrast, in our chemotherapy study, SFN’s effects were only observed behaviorally. These behavioral effects were not accompanied by detectable changes at the protein or microbiome levels, suggesting that dietary SFN may act through non translational or cell type specific mechanisms.

Download

Share

COinS