Oral Intake of Plasticizer Di-(2-ethylhexyl) Phthalate Disrupts Cerebellar Myelination via Thyroid Signaling in Aging Mice

Aging is a significant global health challenge, with neurodegenerative diseases severely affecting the quality of life in the elderly. Di-(2-ethylhexyl) phthalate (DEHP), a commonly used plasticizer in food packaging, has been identified as an environmental contaminant with thyroid hormone (TH) disruption and neurotoxic effects. Myelination in the central nervous system is crucial for neurological function, and oligodendrocytes play a central role in this process by forming myelin around axons. THs regulate oligodendrocyte differentiation and the expression of myelin-related genes. This study investigates whether environmental exposure to DEHP in aging mice disrupts thyroid hormone signaling and contributes to myelin damage. 22-month-old male C57BL/6J mice were orally administered DEHP at doses of 0, 0.2, 20, and 200 mg/kg·bw/day (mg/kg·bw/d) for 30 days (d). Nissl staining revealed significant neuronal loss in the cerebellum at higher DEHP doses. Luxol Fast Blue staining showed notable hypomyelination in DEHP-treated mice. Immunofluorescence results demonstrated an increase in oligodendrocyte progenitor cells (NG2⁺), while mature (CC1⁺) and myelinating oligodendrocytes (MBP⁺) were significantly reduced, indicating impaired oligodendrocyte differentiation and myelination. Furthermore, KLF9, a transcriptional regulator critical for oligodendrocyte differentiation, was downregulated. TH levels (T3, T4), transporters (MCT8, OATP1C1), and receptors (TRα, TRβ) were decreased locally, while deiodinases (DIO2, DIO3) were upregulated, reflecting disruption in thyroid signaling. Environmental exposure to DEHP disrupts thyroid hormone signaling in aged mice, impairing oligodendrocyte differentiation and myelin formation. This process is accompanied by microglial activation and neuroinflammation, which may serve as a pathological basis for neuronal loss and further neurodegeneration. Daily oral intake of plasticizer DEHP may induce cerebellar demyelination, contributing to neurodegeneration in the elderly. These results highlight that inappropriate exposure to environmental pollutants, such as DEHP, could increase the risk of cerebellar dysfunction and neurodegeneration in elderly individuals.