Chapter 8. The Hematologic and Lymphatic Systems
Hematologic & Lymphatic System Disruption: Oncogenic Progression, Immune Burden, and Mitochondrial Collapse
The survivor’s hematologic and lymphatic abnormalities - including testicular cancer metastasis to abdominal lymph nodes and bilateral renal cysts - reflect a toxicant-induced breakdown in immune surveillance, mitochondrial integrity, and lymphoid regulation. These disruptions are mechanistically consistent with chronic permethrin and DEET exposure, particularly through epigenetic reprogramming and mitochondrial impairment in lymphatic tissues.
Clinical Presentation of the Survivor:
• Renal cysts
• 2.25 x 2.3 cm low-density lesion (right kidney)
• 0.6 x 0.5 cm low-density lesion (left kidney)
• Gastrointestinal bleeding
• Urinary tract bleeding
• Metastatic cancer in abdominal lymph nodes
• Lymphadenopathy (transient or persistent swollen lymph nodes)
• Blood cell irregularities
• Mitochondrial dysfunction
Mechanistic Basis of Hematologic & Lymphatic Disruption
1. Mitochondrial Collapse in Lymphoid Tissues (PGC1-α &
NAD⁺ Depletion)
• Disrupts immune cell metabolism and apoptosis regulation.
• Promotes mutation accumulation and failed clearance of
precancerous cells.
2. NF-κB & Wnt Pathway Activation
• Promotes inflammatory remodeling of lymph nodes and bone
marrow.
• Facilitates neoplastic transformation and lymphatic hyperplasia.
3. UPP (Ubiquitin–Proteasome Pathway) Failure
• Inhibits clearance of mutated proteins and lymphoid cells,
fostering metastasis.
4. eNOS & Microvascular Injury
• Impairs lymphatic drainage and oxygenation.
• Creates hypoxic niches favorable for tumor survival and immune
evasion.
5. ERKO & Endocrine–Lymph Node Crosstalk Disruption
• Alters hormone-mediated immune signaling, increasing
metastatic susceptibility in reproductive-organ-linked lymph
nodes.
Renal Cysts & Mitochondrial Dysfunction
• Chronic exposure impairs renal mitochondrial biogenesis,
promoting abnormal epithelial proliferation.
• Renal cyst formation is increasingly recognized as
a mitochondrial phenotype in toxicant-exposed individuals.
• Cysts may contribute to blood pressure variability, filtration
inefficiency, and delayed excretion of metabolic byproducts.
Diagnostic Gaps & Underreporting
• Lymphatic and hematologic issues often dismissed post-cancer
remission, despite lingering mitochondrial and immune
dysfunction.
• Renal cysts misclassified as incidental unless overt loss of f
function occurs.
• Mitochondrial function rarely screened in standard oncology or
other follow-up - missing key indicators of relapse risk, fatigue,
and immune deficit.
Key Insights:
The survivor’s lymphatic metastasis, renal cysts, and systemic mitochondrial dysfunction are not isolated occurrences. They represent a mechanistic continuum of permethrin and DEET toxicity involving mitochondrial collapse, immune escape, and endocrine-laden lymphatic disruption. Early recognition and long-term hematologic and renal surveillance must become standard for chemically exposed veterans and civilians.
Chapter 8 Literature Review:
The Hematologic and Lymphatic Systems
Skinner, Michael K., et al. “Alterations in Sperm DNA Methylation, Non-Coding RNA, and Epigenetic Biomarkers Following Environmental Exposures.” Epigenetics & Chromatin 11, no. 2 (2018): 1–15.
https://doi.org/10.1186/s13072-018-0238-5.
This landmark study by Skinner and colleagues revealed that exposure to common environmental toxicants - such as permethrin - can induce persistent changes in the sperm epigenome, including altered DNA methylation patterns and shifts in non-coding RNA expression. These modifications were shown to be stable, even across generations, and mapped primarily to genes involved in mitochondrial function, immune regulation, and reproductive health. In particular, the study documented epigenetic dysregulation within lymphatic and reproductive tissues, consistent with immune suppression and reproductive toxicity. These mechanisms echo the survivor’s omics-confirmed collapse of mitochondrial structure and function within both testicular and lymphoid compartments. The tissue-specific damage reported in the study aligns with histopathological findings in the survivor’s biopsies, underscoring a central hypothesis of BioSymphony: that mitochondrial compromise initiated by environmental exposures acts as a unifying node in the progression of multi-system disease.
Kubsad, Dyani, et al. “Assessment of Glyphosate-Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations: Generational Toxicology.” Scientific Reports 9 (2019): 6372.
https://doi.org/10.1038/s41598-019-42860-0.
Kubsad et al. examined how glyphosate exposure results in inheritable epigenetic changes - particularly in the sperm epigenome - associated with disease development in unexposed descendants. Notably, they identified disruptions in the Ubiquitin–Proteasome Pathway (UPP), a cellular quality-control mechanism vital for degrading misfolded proteins, maintaining genomic stability, and regulating immune surveillance. Dysregulation of UPP leads to abnormal cell proliferation, impaired apoptosis, and chronic inflammation -all of which contribute to oncogenesis, particularly in lymphatic and reproductive tissues. The survivor’s clinical trajectory includes both testicular malignancy and chronic inflammatory lymphadenopathy, while BioSymphony’s proteomic analysis shows suppression of UPP-related genes and pathways in affected tissues. This study thus strengthens the translational link between pesticide-induced UPP failure and heritable patterns of disease observed across the survivor’s lineage and tissue-specific omics datasets.
Thorson, Jennifer L. M., et al. “Epigenome-Wide Association Study for Pesticide (Permethrin and DEET) Induced DNA Methylation Epimutation Biomarkers for Specific Transgenerational Disease.” Environmental Health 19, no. 1 (2020): 109. https://doi.org/10.1186/s12940-020-00666-y.
In this epigenome-wide association study, Thorson and colleagues identified unique DNA methylation epimutations linked to permethrin and DEET exposure. These epimutations clustered in immune system regulatory genes and were especially enriched in the NF-κB signaling cascade - an inflammatory master switch that controls cytokine expression, cell survival, and immune activation. Aberrant activation of NF-κB is known to underlie chronic inflammatory disorders, autoimmunity, and immune exhaustion. In the survivor’s case, clinical data show repeated inflammatory flares resembling SIRS, extensive lymph node involvement, and elevated biomarkers indicative of NF-κB activation, such as IL-6 and TNF-α. BioSymphony’s analysis further highlights dysregulated methylation of promoter regions controlling NF-κB signaling components across lymphatic, gut, and autonomic tissue samples. This supports the conclusion that immune dysregulation in the survivor is not incidental but rather epigenetically imprinted by toxic exposure and amplified by transgenerational feedback loops.
Navarrete-Meneses, Melany D. P., et al. “Transcriptomic and Epigenomic Changes in Mouse Hematopoietic Tissue Induced by Exposure to Permethrin.” International Journal of Molecular Sciences 24, no. 7 (2023): 6259. https://doi.org/10.3390/ijms24076259.
This 2023 study presents a comprehensive analysis of how permethrin disrupts hematopoietic stem cell (HSC) development in murine models, revealing both transcriptomic silencing and aberrant methylation of genes involved in lineage commitment, immune competence, and inflammation resolution. The most affected pathways included hematopoietic cytokine response, erythroid differentiation, and early lymphoid programming. These impairments suggest a stem-level injury to the regenerative capacity of the immune system. In the survivor’s case, repeated CBC abnormalities - including neutrophilia, lymphopenia, and platelet fluctuation - combine with elevated marrow stress markers and suggest bone marrow exhaustion. BioSymphony’s integrated transcriptomic panel confirms reduced expression of core HSC renewal genes (e.g., GATA2, RUNX1, TET2) in archived blood and marrow samples, further substantiating permethrin as a hematopoietic toxin with long-lasting immune and inflammatory consequences.
Sun, Yu-Jie, et al. “Subchronic Toxicity and Bioaccumulation of Permethrin in Rats.” BMC Pharmacology and Toxicology 23 (2022): 46. https://doi.org/10.1186/s40360-022-00586-2.
Sun et al. demonstrated that repeated low-dose exposure to permethrin led to mitochondrial fragmentation, oxidative stress, and reduced renal perfusion in rats - despite exposure levels deemed environmentally safe. Notably, they observed elevated creatinine and histological evidence of tubular damage, indicating early-stage nephropathy. The study also documented bioaccumulation of permethrin in renal and hepatic tissue, with adverse effects persisting weeks beyond cessation of exposure. The survivor’s clinical records include progressive decline in glomerular filtration rate, cortical hypoperfusion on renal ultrasound, and transcriptomic markers of oxidative stress in kidney biopsies. BioSymphony’s metabolic modeling and tissue-specific toxicant load analysis identify a renal risk profile consistent with permethrin-induced energy crisis and mitochondrial decay. These findings confirm that even subclinical exposure levels can yield substantial bioenergetic and renal impairment, supporting the integration of mitochondrial health as a biomarker class within the BioSymphony platform.
López-Aceves, Teresa G., et al. “Chronic Exposure to Permethrin Induces Mitochondrial Dysfunction and Oxidative Stress in Murine Organs.” Toxics 9, no. 12 (2021): 337. https://doi.org/10.3390/toxics9120337.
López-Aceves and colleagues provided critical insight into the systemic nature of permethrin-induced mitochondrial damage, showing that chronic exposure leads to multi-organ oxidative stress, decreased ATP synthesis, and altered mitochondrial gene expression. Their findings suggest a cumulative toxic load that disrupts metabolic homeostasis across brain, liver, kidney, and reproductive tissues. Mitochondrial ultrastructural abnormalities, ROS overproduction, and reductions in Complex I and Complex IV activities were confirmed in vivo. In alignment with these findings, the survivor’s multi-tissue omics reveal consistent downregulation of mitochondrial respiratory chain genes, increased oxidative DNA damage markers (8-OHdG), and clinical phenotypes of systemic energy failure including fatigue, thermal dysregulation, and post-exertional malaise. These observations support BioSymphony’s model of “mitochondrial chokepoint collapse,” in which persistent environmental exposures deplete cellular energy across organ systems, triggering the cascade of comorbidities seen in complex exposure syndromes like Gulf War Illness.
Chapter 8. Summary Insight
Hematologic and Lymphatic Disruption: Immune Collapse, Renal Compromise, and the Mitochondrial Chokepoint
The survivor’s hematologic and lymphatic pathologies - ranging from renal cyst formation to lymphatic metastasis and persistent blood cell irregularities - are not isolated clinical events. They form a predictable toxicological pattern consistent with chronic permethrin and DEET exposure, compounded by mitochondrial dysfunction and immune system dysregulation.
Lymph node metastasis from testicular cancer, alongside bilateral renal cysts and intermittent gastrointestinal and urinary tract bleeding, signal widespread failure of immune surveillance and cellular housekeeping pathways. These outcomes are mirrored in molecular signatures from the survivor’s omics datasets, including suppressed Ubiquitin–Proteasome Pathway (UPP) activity, altered NF-κB signaling, and mitochondrial collapse confirmed in renal, lymphatic, and reproductive tissues.
Mechanistically, this dysfunction is rooted in mitochondrial depletion, epigenetic silencing of immune-regulatory genes, and toxicant-induced remodeling of lymphoid architecture. The convergence of endocrine-lymphoid cross-talk disruption, eNOS impairment, and Wnt/NF-κB pathway activation creates permissive conditions for oncogenic progression and immune evasion.
Moreover, renal cysts - commonly dismissed as benign - emerge here as evidence of mitochondrial degeneration, oxidative stress, and toxicant bioaccumulation in filtration organs. These cysts compromise kidney function, metabolic clearance, and endocrine signaling, setting the stage for systemic symptom escalation.
BioSymphony’s integrative model - linking omics data, tissue-specific pathology, and toxicogenomic literature - confirms that these hematologic and lymphatic disorders are neither coincidental nor idiopathic. They represent a documented biological trajectory from chronic toxic exposure to immune collapse, vascular fragility, and tumor-supportive microenvironments.
These findings demand urgent updates to post-exposure surveillance and care. Mitochondrial screening, UPP integrity testing, and lymphatic imaging should be standardized in the follow-up of chemically exposed individuals - especially those with histories of malignancy, unexplained immune fatigue, or renal compromise.
As with earlier chapters, this survivor’s case is not anecdotal - it is molecularly validated and clinically replicated. And it reinforces the broader mandate of BioSymphony: to recognize, validate, and treat the hidden legacy of toxic exposure before it cascades into systemic failure.