[CFS] Induced by Environmental Toxic Exposure: Effects of Polyhexamethyleneguanidine Phosphate Exposure on Mitochondrial Function... 2026 Yang et al

[Andy]

Full title: Chronic Fatigue Syndrome Induced by Environmental Toxic Exposure: Effects of Polyhexamethyleneguanidine Phosphate Exposure on Mitochondrial Function and Neural Health.

Highlights​

• PHMG-p contributes to CFS by inducing mitochondrial and neurological dysfunction.
• HD exposure has potential prolonged health effects.
• PHMG-p is a candidate environmental trigger in CFS pathogenesis.

Abstract​

Large-scale human casualties have been reported following exposure to humidifier disinfectants (HDs), with chronic fatigue syndrome (CFS) identified as a potential long-term health outcome. This study aimed to elucidate the mechanistic link between HD exposure and CFS onset, focusing on mitochondrial and neurophysiological dysfunction. Mitochondrial morphology in peripheral blood mononuclear cells (PBMCs) was examined in patients with CFS and documented HD exposure (HD-CFS).

To validate clinical findings, polyhexamethyleneguanidine-phosphate (PHMG-p), a major HD component, was intratracheally administered to mice, which were then subjected to fatigue-related behavioral assessment. In PBMCs, mitochondrial morphology, membrane potential, oxidative phosphorylation (OXPHOS) protein expression, and transcriptomic alterations were assessed. Brain tissues were evaluated for neuroglial activity, blood–brain barrier (BBB) integrity, and OXPHOS protein expression. PBMCs from patients with HD-CFS exhibited significantly increased mitochondrial abnormalities.

In mice, PHMG-p exposure caused mitochondrial abnormalities, decreased the expression of OXPHOS complexes, and downregulated the expression of genes related to mitochondrial membrane potential. Neurological assessments revealed glymphatic dysfunction, BBB disruption, and reduced OXPHOS complex expression in the hypothalamus. These findings suggest that PHMG-p contributes to CFS pathogenesis by inducing mitochondrial and neurological dysfunction.

This study highlights the potential long-term health risks of HD exposure and identifies PHMG-p as a candidate environmental trigger in CFS.

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[SNT Gatchaman]

In South Korea, widespread use of HDs prior to 2011 resulted in significant health consequences due to inhalation exposure. HD exposure exerts adverse effects not only on the respiratory system but also on the nervous system. Notably, the health impairments associated with HD exposure have persisted for more than a decade following cessation of use, with many affected individuals continuing to report chronic fatigue and diminished health-related quality of life.

The incidence of chronic fatigue syndrome (CFS) among individuals exposed to HDs is 12.93%, which is 14.5 times higher than the global CFS incidence of 0.89%

Twenty-four individuals with a history of HD exposure and reported CFS symptoms (HD-CFS) were recruited from specialty clinics and support groups for victims exposed to HDs in South Korea.

All participants were aged between 9 and 50 years. CFS was diagnosed based on one of the following three widely accepted diagnostic criteria: (1) the 1994 data in the Centers for Disease Control and Prevention (also known as the “Fukuda” criteria) (Fukuda et al., 1994), (2) the 2003 Canadian Consensus Criteria (Carruthers et al., 2003), and (3) the 2011 International Consensus Criteria (Carruthers et al., 2011).

The cohort included individuals aged 9–39 years (mean: 17 years), and PBMCs were sampled approximately 9 years after the cessation of HD exposure. From this, we can infer that HD exposure occurred between the approximate ages of 0 and 30 years.

 

[SNT Gatchaman]

I can't see that they've specified which or how many patients qualified under any of the three criteria: Fukuda, CCC, ICC.

Similarly they don't give the Bell score, instead —

For intuitive understanding, we utilized the inverse score of the Integral CFS Ability Scale investigated in humans, with a higher score indicating a more severe fatigue state. The inverse score was obtained by subtracting the investigated score from the maximum score of 10 on the Integral CFS Ability Scale.

(All but milder 3 M and 2 F were in the 4-7 range)

 

[SNT Gatchaman]

In the PBMCs from the PHMG-p-exposed mice, we observed pronounced mitochondrial morphological alterations, accompanied by reductions in respiratory chain complexes II and III, cytochrome c, mitochondrial membrane potential, and the expression of genes regulating mitochondrial membrane potential.

Compared with those in the control group, the PBMC mitochondria in the HD-CFS group exhibited indistinct or disrupted inner and outer mitochondrial membranes. […] However, no significant correlation was found between fatigue severity and mitochondrial abnormality scores within the HD-CFS group, and mitochondrial size did not differ significantly between the two groups.

The mice exposed to PHMG-p showed hypothalamic dysfunction, as evidenced by double-positive immunofluorescent signals for GFAP/AQP4 (glymphatic dysfunction) and claudin 5/CD31 (BBB disruption), but not microglial alterations. […] As a result of these hypothalamic dysfunctions, plasma corticosterone levels significantly increased after 15 min of forced exercise compared with their respective controls and were further augmented in the mice exposed to PHMG-p, indicating impaired hypothalamic–pituitary–adrenal gland (HPA) feedback loop. In addition, the mitochondrial complex I expression of the hypothalamic homogenate significantly decreased in the PHMG-p-exposed mice by nearly half compared with that in the controls.

PHMG-p disrupts epithelial integrity by damaging tight junctions and the F-actin cytoskeleton. Cytoskeletal components and adhesion proteins are essential for maintaining BBB integrity; hence, their disruption can significantly increase BBB permeability. These reports support our finding that the expression of [claudin-5], a tight junction molecule of the BBB, was downregulated by PHMG-p administration, ultimately suggesting that PHMG-p affects permeability through the collapse of the BBB.

a significant reduction in the astrocytic glymphatic system of the hypothalamus and an exaggerated corticosterone response of the HPA axis were observed in the PHMG-p-exposed mice, without changes in microglial neuroinflammation. These findings are notable given that HPA axis dysfunction and autonomic dysregulation are central features in CFS pathophysiology. Intriguingly, we observed mitochondrial dysfunction, particularly reduced expression of respiratory chain complex I, in the hypothalamus.

To determine whether PHMG-p-induced mitochondrial abnormalities observed in PBMCs also occur in other high-energy-demand tissues, we examined mitochondrial morphology in skeletal muscle. […] no apparent morphological abnormalities in muscle mitochondria were detected…

They speculate on bone marrow and effects on stem cells via cytokines.

PHMG-p exposure is associated with sustained increases in multiple inflammatory cytokines and chemokines. Taken together with the findings of the present study, these pathological features raise the possibility that PHMG-p-induced injury influences the bone marrow microenvironment, thereby perturbing HSC differentiation and leading to the generation of blood cells with altered functional or metabolic properties.

 

[SNT Gatchaman]

Cytoskeleton derangement is implicated with organophosphates more generally —

The Neuronal Cytoskeleton as a Potential Target in the Developmental Neurotoxicity of Organophosphorothionate Insecticides (2014, Basic & Clinical Pharmacology & Toxicology)

Spoiler: Abstract

Phosphorothionates are toxicologically the most important class of organophosphorus ester (OP) insecticides. Phosphorothionates are metabolically converted in vivo to their oxon analogues. These oxon metabolites can bind and inhibit acetylcholinesterase, thus causing acute cholinergic neurotoxicity. Oxon binding to the same target may also be partly responsible for manifestation of the ‘intermediate syndrome’. More recent evidence suggests that the oxons may be also capable of inducing developmental neurotoxicity. The neuronal cytoskeleton may represent a potential target for the developmental neurotoxicity of the oxons because of its vital importance in many stages of normal neurodevelopment.

Data obtained in the last five years and critically reviewed here indicate that the oxon metabolites, at concentrations that can be attained in vivo, exert potent effects on the neuronal cytoskeleton disrupting all three cytoskeletal networks. This disruption is expressed at the level of cytoskeletal protein expression, intracellular distribution, post-translational modification, cytoskeletal dynamics and function and may involve effects on both neuronal and glial cells.

These effects are not secondary to other changes but may constitute primary effects of the oxons, as these compounds have been shown to be capable of covalently binding to and organophosphorylating multiple sites on tubulin and actin.

Analogous studies must be extended to include other neurodevelopmentally important cytoskeletal proteins, such as neurofilament heavy chain, and tau, which are known to contain unusually high numbers of phosphorylatable sites and to establish whether organophosphorylation by the oxons takes place at sites where neurodevelopmentally relevant, endogenous, reversible phosphorylation is known to occur.

The cytoskeleton as a non-cholinergic target of organophosphate compounds (2021, Chemico-Biological Interactions)

Spoiler: Abstract

Current organophosphate (OP) toxicity research now considers potential non-cholinergic mechanisms for these compounds, since the inhibition of acetylcholinesterase (AChE) cannot completely explain all the adverse biological effects of OP. Thanks to the development of new strategies for OP detection, some potential molecular targets have been identified.

Among these molecules are several cytoskeletal proteins, including actin, tubulin, intermediate filament proteins, and associated proteins, such as motor proteins, microtubule-associated proteins (MAPs), and cofilin. in vitro, ex vivo, and some in vivo reports have identified alterations in the cytoskeleton following OP exposure, including cell morphology defects, cells detachments, intracellular transport disruption, aberrant mitotic spindle formation, modification of cell motility, and reduced phagocytic capability, which implicate the cytoskeleton in OP toxicity.

Here, we reviewed the evidence indicating the cytoskeletal targets of OP compounds, including their strategies, the potential effects of their alterations, and their possible participation in neurotoxicity, embryonic development, cell division, and immunotoxicity related to OP compounds exposure.

HIGHLIGHTS
• Cytoskeleton and related proteins are non-cholinergic targets for organophosphates.

• Organophosphates exposure can modify cytoskeleton-dependent cell functions.

• Cytoskeleton disruption may be related to chronic organophosphates exposure effects.

 

[alktipping]

Wondering how much of this led to so called sick building syndrome in Europe.

 

[ScoutB]

Is there a source for this?

The incidence of chronic fatigue syndrome (CFS) among individuals exposed to HDs is 12.93%, which is 14.5 times higher than the global CFS incidence of 0.89%

 

[SNT Gatchaman]

Among 4,410 individuals for correlation between HD exposure and disease, 570 individuals (12.93%) met the diagnostic criteria for CFS, as reported by the National Institute of Environmental Research (NIER, 2020). Notably, this prevalence is approximately 14.5 times higher than the global population estimate of CFS (0.89%), as reported in a recent metaanalysis (Lim et al., 2020).

National Institute of Environmental Research (NIER), 2020. Study for Improving Recognition and Judgement Standard of Health Damage of Humidifier Disinfectants (Ⅲ). NIER-SP2020053, p74-100 (in Korean).

Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis CFS/ME (2020)