# Epigenetic Dysregulation, Genetic Mutations, And Outcomes Of Lymphoid Malignancies Related To Agent Orange And Burn Pit Exposures Compared To Unexposed Case-Matched Controls

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Environmental carcinogens, such as Agent Orange (AO) and smoke from burn pits, are important exposures to
the military and civilian populations in theaters of conflict and have been related to development of lymphoid
malignancies. AO was an herbicide that was contaminated with the carcinogenic 2,3,7,8-tetrachlorodibenzo-p-
dioxin (TCDD) as a byproduct during synthesis. AO was used to deforest the jungles of Vietnam and the
demilitarized zone of Korea. Though AO is no longer used, its impact remains relevant because of its long half-
life of almost ten years and its detection in human serum even after 20 years. Preclinical studies show that
activation of the aryl hydrocarbon receptor (AHR, the dioxin receptor) pathway leads to the development of
lymphoid malignancies because of inhibition of apoptosis and/or immune suppression. Secondly, chronic
exposure to TCDD dysregulates epigenetic functions by altering the transcription of pathophysiologically
important proteins involved in oncogenesis. Finally, another interesting connection can be made on the basis of
sex. Lymphoid malignancies are universally more prevalent in men compared to women, but the mechanism is
poorly understood. One reason could be that estrogen may exert protective hormonal effects. Dioxin exposure
and activation of the AHR pathway has been associated with decreased levels of estrogen receptor (ER) due to
binding between AHR and ER, increased degradation of ER, and upregulation of CYP1A1, which mediates
estrogen metabolism. Together, these mechanism(s) may form the pathophysiological basis for the increased
incidence and poorer clinical outcomes of lymphoid malignancies following environmental exposures.
We hypothesize that if chemical carcinogens alter epigenetic regulation in the development and progression of
lymphoid malignancies, then these patients will have mutations in epigenetic genes or exhibit a greater degree
of change in DNA methylation of pathophysiologically relevant genes in the tumor tissue compared to controls.
These findings can be used as biomarkers to identify who may benefit from treatment with targeted therapies in
future studies. Currently there are approved epigenetic treatments for hematologic malignancies with
hypomethylating agents and/or histone deacetylase inhibitors, which could be tailored to patients who will most
likely benefit. We will test our hypothesis via three specific aims. Specific Aim 1 (SA1): Create a predictive model
using the clinical and genetic database from the prospective Million Veterans Program to determine which risk
factors are likely to contribute to the development of lymphoid malignancies. Patients who enroll fill out surveys
about medical history, military exposures, lifestyle, and medications and submit blood for genomic sequencing,
which are relevant to our hypothesis. In addition, data from VA medical records and the National Death Index
are available to fully explore the patient exposome. Specific Aim 2 (SA2): Use exi...

## Key facts

- **NIH application ID:** 10907413
- **Project number:** 5IK2CX002437-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Helen Ma
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907413

## Citation

> US National Institutes of Health, RePORTER application 10907413, Epigenetic Dysregulation, Genetic Mutations, And Outcomes Of Lymphoid Malignancies Related To Agent Orange And Burn Pit Exposures Compared To Unexposed Case-Matched Controls (5IK2CX002437-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10907413. Licensed CC0.

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