Natural bioactive compounds as therapeutic agents against phthalate neurotoxicity: Cellular and molecular signaling...

Phthalates are ubiquitous environmental contaminants and endocrine-disrupting chemicals used as plasticizers in consumer products, medical devices, and industrial materials. Evidence from in vitro experiments, animal models, and epidemiological studies suggests that phthalate exposure, particularly to di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and benzyl butyl phthalate (BBP), may induce neurotoxicity through multiple interconnected mechanisms. The developing brain is especially vulnerable, with prenatal and early-life exposures linked to cognitive deficits, behavioral abnormalities, and neurodevelopmental disorders. Conventional therapeutic options remain limited, highlighting the need for effective neuroprotective strategies. Natural bioactive compounds such as polyphenols, flavonoids, carotenoids, and other phytochemicals have been investigated as potential neuroprotective candidates in preclinical models owing to their multi-target mechanisms (e.g., antioxidant, anti-inflammatory, and neurotrophic actions), potent antioxidant capacity, and regulation of cellular signaling pathways. Preclinical studies demonstrate that lycopene, ferulic acid, coenzyme Q10, omega-3 fatty acids, vanillic acid, and Moringa oleifera extracts attenuate phthalate-induced neurotoxicity by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway, suppressing nuclear factor-kappa B (NF-κB)-mediated inflammation, modulating MAPK/ERK and PI3K/Akt signaling, and restoring brain-derived neurotrophic factor (BDNF)/TrkB support. Despite these promising findings, challenges persist, including poor bioavailability, lack of standardized dosing, and limited human clinical trials. A structured review of experimental and epidemiological studies was conducted using predefined inclusion criteria. This review integrates evidence across in vitro, in vivo, and human studies to identify key mechanisms of phthalate-induced neurotoxicity, including oxidative stress, neuroinflammation, endocrine disruption, epigenetic dysregulation, and impaired neuroplasticity, and evaluates pathway-specific neuroprotective actions of bioactive compounds while highlighting critical translational gaps.