Organophosphate esters (OPEs) are organic esters of phosphoric acid containing either alkyl chains or aryl groups. Based on their side chain substituents, OPEs are categorized into several groups, including chlorinated OPEs (Cl-OPEs), alkyl OPEs, brominated OPEs (Br-OPEs), and aryl OPEs [1,2]. Due to their effectiveness in reducing flammability or enhancing plasticity in polymers, OPEs are widely employed as flame retardants (FRs), with plasticizer applications projected to dominate the global market over the next five years [3,4]. Reported consumption of OPEs (used solely as FRs) in Western Europe reached approximately 91,000 tons in 2006, representing a 7% increase compared to 2005 [5]. Another study indicated that in 2020, OPE production in China reached 363,003 tons, accounting for 61% of the total organophosphate flame retardants (OPFRs) [6]. Consequently, OPEs have raised growing environmental concerns in recent years [6]. However, most OPEs are incorporated as additives rather than being chemically bound to products. Therefore, they are readily released into the environment through abrasion, dissolution, and volatilization [[7], [8], [9]] and subsequently enter human exposure pathways, such as dermal contact, dust ingestion, inhalation, and dietary intake [10,11].

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is now one of the most commonly used flame retardants [12]. As an additive flame retardant, TDCPP can be released into the environment through various pathways [13]. It is ubiquitous in environmental media, biological matrices, and the human body and is therefore considered an emerging environmental contaminant [14]. TDCPP does not readily degrade in water, tends to accumulate continuously in the environment, and is frequently detected in indoor dust, air, water, and soil [14]. Following the widespread detection of TDCPP in numerous human samples, both TDCPP and its primary diester metabolite, bis(1,3-dichloro-2-propyl) phosphate (BDCPP), have been detected in human seminal plasma, breast milk, plasma, placenta, and urine, raising significant concern regarding the potential human health effects of exposure to this chemical. In recent years, TDCPP has been demonstrated to exert diverse toxic effects on organisms, including neurotoxicity, reproductive and developmental toxicity, hepatotoxicity, endocrine disruption, and carcinogenicity [[15], [16], [17], [18], [19]].

Recently, the neurotoxicity induced by TDCPP has garnered significant attention. Experimental studies have demonstrated that TDCPP can induce neurobehavioral abnormalities, neuronal damage, and neurotransmitter dysregulation at environmentally relevant concentrations. For instance, TDCPP exposure significantly inhibited head-shaking frequency, body-bending frequency, and chemotactic behavior in C. elegans through oxidative stress-induced dopaminergic neuron damage [20,21]. In zebrafish, larval exposure reduced motor behavior, and early exposure led to anxiety-like behavior in adulthood ([22]; Qian et al., 2022b). In mammalian models, TDCPP exposure caused hippocampal neuronal damage and impaired learning and memory in mice, while Long-Evans rats exhibited behavioral abnormalities, including prolonged floating time in the Morris water maze and altered forelimb grip strength [23,24]. Population-based epidemiological evidence indicates that TDCPP exposure is significantly associated with cognitive decline in elderly populations [25]. Furthermore, prenatal exposure has been linked to neurodevelopmental delays and dose-dependent IQ declines in children, as observed in studies from Wuhan, China, and the CHAMACOS cohort [26,27]. Notably, studies suggest that TDCPP exacerbates Parkinson's disease (PD)-related neurotoxicity via ferroptosis-associated oxidative stress and neuroinflammatory mechanisms [28]. However, a systematic and mechanistic understanding of how TDCPP exposure contributes to PD pathogenesis, particularly at the molecular and cellular level, remains largely elusive.

Traditional toxicological studies, while valuable, often face limitations in holistically deciphering complex chemical-biological interactions. The emerging paradigm of network toxicology, which integrates bioinformatics, systems biology, and computational simulations, offers a powerful framework for predicting chemical toxicity and formulating testable mechanistic hypotheses (Del Giudice et al., 2024). This approach is increasingly recognized for its utility in elucidating mechanisms of environmental neurotoxicants ([29]; Sachchida., 2021). However, the predictive power of such in silico approaches ultimately requires validation through targeted experimental models. Therefore, a strategy that seamlessly integrates computational prediction with experimental verification is crucial for establishing credible mechanistic links between environmental exposures and chronic diseases like PD.

Therefore, this study employed an integrated strategy combining network toxicology, molecular docking, in vivo experimental validation, and molecular dynamics simulations. This multi-faceted approach was designed to systematically decipher the molecular interactions and pathological pathways through which TDCPP contributes to Parkinson's disease (PD) via the direct targeting and upregulation of EPAS1 within the neurovascular unit, and to identify its core protein target. Our findings aim to provide mechanistic insights for the risk assessment of environmental pollutants and to establish a scientific basis for future preventive strategies.