Phthalates are ubiquitous environmental contaminants and endocrine-disrupting chemicals used as plasticizers in consumer products, medical devices, and industrial materials. Evidence from in vitro exp Show more
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. Show less
Phthalates are well-known emerging contaminants in the environment and food packaging, posing serious risks to human health as endocrine disruptors with significant neurotoxic potential. Epidemiologic Show more
Phthalates are well-known emerging contaminants in the environment and food packaging, posing serious risks to human health as endocrine disruptors with significant neurotoxic potential. Epidemiological and experimental evidence have linked early-life phthalate exposure to neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the precise molecular mechanisms responsible for these associations remain poorly understood. This study aimed to comprehensively investigate the putative toxic targets and molecular pathways underlying phthalate-induced ADHD and ASD through integrated network toxicology and molecular docking approaches. Targets related to phthalates, ADHD, and ASD were extracted from various databases, yielding 21 potential targets associated with ADHD and ASD, which are common to the studied phthalates. Network analysis highlighted BDNF and ESR1 as the top two core targets. Functional enrichment analyses demonstrated that the core targets are involved in multiple pathways. Furthermore, the GEO database was queried to identify differentially expressed genes (DEGs) and gene modules through Weighted Gene Co-expression Network Analysis (WGCNA) using the R package. Moreover, molecular docking demonstrated high binding affinity between phthalates and core targets, with di(2-ethylhexyl) phthalate with BDNF and diisononyl phthalate with ESR1, emphasizing the potential role of phthalate exposure in neurodevelopmental disorders. The stability of these complexes was demonstrated through molecular dynamics simulations, which confirmed their binding interactions remained constant throughout the simulation. Our findings contribute to a deeper understanding of the intricate molecular mechanisms of phthalate-induced neurotoxicity, offering a valuable foundation for the development of future therapeutic strategies to mitigate their adverse effects on neurodevelopment. Show less