Di(2-ethylhexyl) phthalate (DEHP)-induced circadian disruption accelerates aging-related functional declines via oxidative stress and insulin/IGF-1 signaling in Caenorhabditis elegans.

Circadian disruption is increasingly linked to adverse health outcomes, yet its mechanistic role in age-related functional decline under environmental exposure remains unclear. This study investigated whether di(2-ethylhexyl) phthalate (DEHP), a ubiquitous environmental plasticizer and well-established endocrine disruptor, accelerates aging-related functional declines through circadian disruption in Caenorhabditis elegans. Exposure to DEHP (5 μg/mL) under disrupted temperature-entrained rhythms significantly increased reactive oxygen species, reduced oxidative stress resistance, and impaired healthspan(definition) indicators, evidenced by decreased pharyngeal pumping and increased intestinal lipofuscin accumulation in aged animals. Antioxidant treatment with N-acetylcysteine partially alleviated these effects, supporting a key role for oxidative stress. Molecular docking and genetic analyses further demonstrated the involvement of insulin/IGF-1 signaling, with DEHP suppressing oxidative stress-induced nuclear translocation of DAF-16. Mutations in pathway genes attenuated DEHP-induced phenotypes. Collectively, these findings establish a mechanistic link between environmental phthalate exposure, circadian disruption, and aging-related functional declines mediated by oxidative stress and insulin/IGF-1 signaling.