Chronic fatigue syndrome induced by environmental toxic exposure: Effects of polyhexamethyleneguanidine phosphate exposure on mitochondrial function and neural health.

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.