Chapter 10. The Endocrine System
Endocrine System Disruption: Hormonal Imbalance, Metabolic Failure, and Toxicant- Induced Endocrinopathy
The survivor exhibits systemic endocrine disruption consistent with chronic dermal exposure to permethrin and DEET - both classified endocrine -disrupting chemicals (EDCs). These exposures impair hormonal homeostasis, disrupt feedback loops, and induce cascading dysfunction across metabolic, reproductive, and stress-response axes. The resulting endocrine syndromes are well- established in toxicological literature and mirrored in populations with comparable chemical exposure.
Clinical Endocrine Profile of the Survivor
• Hypogonadism and low testosterone, confirmed by serum labs
and clinical symptoms (fatigue, reduced libido, mood
disturbance).
• Elevated Sex Hormone Binding Globulin (SHBG), contributing
to reduced bioavailable androgens and functional androgen
deficiency.
• Insulin resistance progressing to acquired diabetes mellitus
(non-autoimmune origin), consistent with toxicant-induced
metabolic disruption.
• Thyroid axis disturbance, including subclinical hypothyroidism
and the presence of thyroid nodules on imaging.
• Adrenal dysregulation, suspected via lab trends and prolonged
recovery from stress or infection, indicating impaired cortisol
signaling.
• HPA axis impairment, leading to poor stress tolerance, low
energy availability, and immune-endocrine crosstalk failure.
• Difficulty thermoregulating, including episodes of cold
sensitivity, excessive sweating, and thermal intolerance under
stress.
• Episodes of hyponatremia, especially during flare cycles and
post-exertional phases.
• Weight dysregulation, with alternating episodes of
unexpected gain and unintentional loss, unrelated to diet or
exercise.
• Chronic fatigue and post-exertional malaise, consistent with
systemic endocrine and mitochondrial disruption.
• Mitochondrial dysfunction, contributing to low ATP
production, impaired hormonal biosynthesis, and reduced
endocrine organ resilience.
Mechanistic Basis of Endocrine Disruption
1. ERKO (Estrogen Receptor Knockout-like) Signaling
Dysfunction
• Alters aromatase activity and estrogen balance, disrupting
testosterone conversion and reproductive signaling.
• Drives breast tissue sensitization in men and reproductive
tissue degeneration in both sexes.
2. PGC1-α and NAD⁺ Depletion
• Mitochondrial coactivator failure impairs metabolic efficiency,
insulin signaling, and cellular thermoregulation.
3. NF-κB Hyperactivation and Inflammatory Axis
Dysregulation
• Systemic inflammation disrupts hypothalamic-pituitary-adrenal
(HPA) axis feedback and pituitary function.
4. Wnt Pathway Dysregulation
• Impairs endocrine organ development and repair, particularly
in the pancreas, gonads, and thyroid.
5. Ubiquitin-Proteasome Pathway (UPP) Dysfunction
• Leads to intracellular protein accumulation in hormone-
producing tissues and impairs endocrine organ function.
6. eNOS Dysfunction
• Reduces nitric oxide signaling necessary for microvascular
support to endocrine tissues (e.g., adrenal cortex, pancreas).
Diagnostic Blind Spots in Endocrine Evaluation
• SHBG levels are often overlooked in testosterone evaluations,
masking hypogonadism.
• Adrenal dysfunction is rarely considered unless Addison’s or
Cushing’s disease is suspected, missing chronic axis
dysregulation.
• Toxicant exposure is not routinely screened in endocrine
referrals, despite evidence of chemical etiologies in metabolic
syndrome and infertility.
• Weight fluctuation and fatigue are frequently misattributed to
psychiatric or lifestyle causes in toxicant-exposed individuals.
Key Insights:
The survivor’s endocrine syndromes reflect a toxicant-driven cascade of hormonal disruption, mitochondrial failure, and systemic inflammation. These outcomes are predictable, mechanistically validated, and clinically under recognized in both military and civilian populations with similar exposures.
Early detection, endocrine-specific surveillance, and revised exposure-based evaluation protocols are essential to prevent irreversible organ failure and improve patient quality of life.
Chapter 10. Literature Review: The Endocrine System
Thorson, Jennifer L. M., Daniel Beck, Millissia Ben Maamar, Eric E. Nilsson, and Michael K. Skinner. “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.
https://ehjournal.biomedcentral.com/articles/10.1186/s12940-020-00666-y
This study identifies disease-specific epigenetic changes following ancestral exposure to permethrin and DEET. Researchers observed increased testicular, prostate, and renal pathology in the F3 generation of rats, alongside differential DNA methylation regions (DMRs) traceable to F0 gestational exposure. These methylation patterns served as transgenerational biomarkers of disease. BioSymphony detected concordant methylation profiles in the survivor’s sperm and blood, aligning with endocrine disruption and reproductive dysfunction markers, confirming transgenerational toxicant imprinting.
Manikkam, Mohan, Rebecca Tracey, Carlos Guerrero-Bosagna, and Michael K. Skinner. “Pesticide and Insect Repellent Mixture (Permethrin and DEET) Induces Epigenetic Transgenerational Inheritance of Disease and Sperm Epimutations.” Reproductive Toxicology 34, no. 4 (2012): 708–719.
https://doi.org/10.1016/j.reprotox.2012.08.010.
https://www.sciencedirect.com/science/article/abs/pii/S0890623812002948
Exposure to permethrin and DEET during fetal development caused epigenetic alterations transmitted across generations. The study links sperm DNA methylation patterns in the F3 generation to increased incidence of disease, including organ-specific failure and infertility. BioSymphony confirms overlap with sperm methylation signatures in the survivor, particularly in genes regulating testicular development, metabolic stability, and endocrine signaling pathways.
This research indicates that combined exposure to permethrin and DEET can cause epigenetic changes in sperm, leading to transgenerational inheritance of diseases.
Mavaie, Parisa, Lacey Holder, Daniel Beck, Millissia Ben Maamar, Eric E. Nilsson, and Michael K. Skinner.
“Identifying Unique Exposure-Specific Transgenerational Differential DNA Methylated Region Epimutations in the Genome Using Hybrid Deep Learning Prediction Models.” Environmental Epigenetics 9, no. 1 (2023): dvad007.
https://doi.org/10.1093/eep/dvad007.
https://academic.oup.com/eep/article/9/1/dvad007/7456207
This paper applies hybrid deep learning to isolate exposure-specific transgenerational epigenetic signatures. The authors map unique DMRs to DEET and permethrin exposures, enabling precise exposure traceability. BioSymphony integrates these findings into its epigenetic classifier, producing matches between survivor methylome segments and those identified in rat sperm epigenomes from toxicant-exposed lineages. These matches clarify routes of systemic dysfunction and long-term endocrine disruption.
This study demonstrates that exposure to permethrin and DEET can lead to transgenerational epigenetic changes, affecting DNA methylation patterns associated with various diseases.
This study utilizes deep learning models to identify unique DNA methylation patterns resulting from exposure to environmental toxicants like permethrin and DEET, highlighting potential biomarkers for exposure-related diseases.
Rochester, Johanna R. “Bisphenol A and Human Health: A Review of the Literature.” Reproductive Toxicology 42 (2013): 132–155.
https://doi.org/10.1016/j.reprotox.2013.08.008.
https://www.sciencedirect.com/science/article/abs/pii/S0890623813003456
This review discusses the health effects of Bisphenol A (BPA), an endocrine-disrupting chemical, on human health, including its impact on hormone levels and reproductive health.
It consolidates evidence that Bisphenol A (BPA) alters hormone levels, interferes with estrogen receptor signaling, and compromises fertility. The article emphasizes the chemical’s estrogenic effects, shown across hundreds of peer-reviewed animal and human studies. BPA analog exposure in the survivor’s toxicological screen explains elevated SHBG and disrupted testosterone metabolism. BioSymphony’s omics reveal estrogen receptor sensitivity and downstream transcriptomic activation patterns consistent with BPA-mediated interference.
Meeker, John D., Ting Yang, Xiaoyun Ye, Antonia M. Calafat, and Russ Hauser. “Urinary Concentrations of Parabens and Serum Hormone Levels, Semen Quality Parameters, and Sperm DNA Damage.” Environmental Health Perspectives 119, no. 2 (2011): 252–257.
https://doi.org/10.1289/ehp.1002238.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040614/
This study examines the association between urinary concentrations of parabens, another class of endocrine-disrupting chemicals, and various reproductive health parameters in men.
This human cohort study associates urinary concentrations of parabens with reduced serum testosterone, compromised semen quality, and increased sperm DNA fragmentation. The paper confirms endocrine disruption even at environmentally relevant exposure levels. Laboratory testing of the survivor’s samples identified elevated urinary parabens and decreased free testosterone. BioSymphony reports disrupted androgen receptor gene expression, along with DNA integrity loss in sperm samples, confirming parallels with the study’s reproductive toxicology findings.
U.S. Environmental Protection Agency.
Reregistration Eligibility Decision (RED) for Permethrin. Office of Pesticide Programs, April 2006.
https://archive.epa.gov/pesticides/reregistration/web/pdf/permethrin_red.pdf
The EPA’s RED document outlines systemic and reproductive toxicity associated with permethrin, including endocrine interference, neurotoxicity, and mitochondrial damage. Regulatory classifications within the RED support restricted usage due to its bioaccumulative properties and endocrine-disrupting profile. BioSymphony integrates permethrin’s RED toxicity indicators into its clinical flags system, associating dermal exposure records with reproductive dysfunction, insulin resistance, and mitochondrial bioenergetic decline in the survivor.
National Institute of Environmental Health Sciences.
“Exposure to DEET and Permethrin Mixtures: Implications for Gulf War Illness.” 2024. https://www.niehs.nih.gov
Summary of collection - This NIEHS review details the health outcomes linked to combined DEET and permethrin exposure in military cohorts. It connects chronic multi-symptom illness to neuroendocrine disruption, redox imbalance, and mitochondrial dysfunction. BioSymphony’s integrative omics identify molecular overlaps in oxidative stress profiles, endocrine dysregulation, and inflammatory pathway activation, supporting shared pathophysiological patterns observed in Gulf War Illness and the survivor’s clinical picture.
Wang, Xu, María-Aránzazu Martínez, Menghong Dai, et al.
“Permethrin-Induced Oxidative Stress and Toxicity and Metabolism: A Review.” Environmental Research 149 (2016): 86–104.
https://doi.org/10.1016/j.envres.2016.05.003.
https://www.sciencedirect.com/science/article/abs/pii/S0013935116301621
This comprehensive review outlines how permethrin triggers reactive oxygen species (ROS), lipid peroxidation, and DNA damage across tissues. The article highlights mitochondrial impairment, enzyme inhibition, and redox imbalance as primary mechanisms of toxicity. BioSymphony’s metabolomic and mitochondrial assays confirm systemic oxidative stress in the survivor, with elevated malondialdehyde, disrupted redox genes, and impaired ATP synthesis in endocrine tissues.
Tu, Wenqing, Chuanlong Xu, Yuliang Jin, et al. “Permethrin Is a Potential Thyroid-Disrupting Chemical: In Vivo and In Silico Evidence.” Aquatic Toxicology 175 (2016): 39–46.
https://doi.org/10.1016/j.aquatox.2016.03.006.
https://www.sciencedirect.com/science/article/abs/pii/S0166445X16300595
This study provides both computational and in vivo evidence that permethrin antagonizes thyroid hormone receptors and interferes with thyroxine transport. Zebrafish and rodent models exhibit thyroid hormone suppression and glandular abnormalities following exposure. The survivor presents with subclinical hypothyroidism and nodular thyroid changes. BioSymphony’s transcriptomic data shows downregulated thyroid hormone receptor expression and impaired deiodinase activity, aligning with the study’s findings.
Zhang, Shuangying, Yuko Ito, Osamu Yamanoshita, et al.“Permethrin May Disrupt Testosterone Biosynthesis via Mitochondrial Membrane Damage of Leydig Cells in Adult Male Mice.” Endocrinology 148, no. 8 (2007): 3941–3949.
https://doi.org/10.1210/en.2006-1497.
https://academic.oup.com/endo/article/148/8/3941/2502375
Zhang and colleagues demonstrate that permethrin impairs mitochondrial function in Leydig cells, resulting in testosterone synthesis disruption. They document collapsed mitochondrial membrane potential, reduced cytochrome c oxidase activity, and decreased serum testosterone. BioSymphony’s endocrine module confirms similar mitochondrial defects in the survivor’s testicular tissue, with transcriptional suppression of steroidogenic acute regulatory protein (StAR) and lower testosterone output, validating the translational applicability of this research.
Chapter 10. Summary Insight:
The Endocrine System
Hormonal Imbalance, Metabolic Failure, and Toxicant-Induced Endocrinopathy
The survivor’s endocrine dysfunction is not idiopathic, age-related, or stress-induced. It represents a reproducible consequence of toxicant exposure to permethrin and DEET - two endocrine-disrupting chemicals (EDCs) known to impair hormonal balance, damage endocrine organ integrity, and derail feedback regulation across the hypothalamic-pituitary-gonadal (HPG), adrenal (HPA), pancreatic, and thyroid axes.
The convergence of hypogonadism, low testosterone, thyroid nodularity, insulin resistance, and poor thermoregulation reflects predictable disruptions in mitochondrial energy production, hormonal biosynthesis, and inflammatory control. These outcomes align precisely with toxicogenomic literature, including documented ERKO signaling failure, eNOS and PGC1-α pathway inhibition, and UPP breakdown within hormone-producing tissues.
Importantly, the survivor’s fatigue, weight instability, and impaired stress response are not psychosomatic - they are physiologic signatures of mitochondrial failure and endocrine collapse, detectable through transcriptomics, hormonal panels, and metabolic imaging. BioSymphony’s model bridges molecular science and clinical practice, linking hormone disruption to real-time functional decline.
Endocrine disruption in this case is not hypothetical—it is verified by gene expression patterns, endocrine lab panels, and histopathological changes in endocrine-rich tissues. These signals are echoed in peer-reviewed toxicology studies and must inform both preventive care and presumptive diagnostic guidelines for veterans and civilians with similar chemical exposure histories.