Developmental and Neurobehavioral Toxicity of Hexaphenoxycyclotriphosphazene: Implications for Its Safety as a Flame-Retardant Alternative to Triphenyl Phosphate
Ruobing Bai, Hongyi Xian, Yu Feng, Xiyun Huang, Shiyue Tang, Zhiming Li, Long Zhang, Yizhou Zhong, Wanyan Wu, Jiangpeng Tang, Chudan Gao, Li Yan, Xinguang Zhong, Da Chen, Zhenlie Huang
Abstract
Hexaphenoxycyclotriphosphazene (HPCTP) has been introduced as a halogen-free replacement for the flame-retardant triphenyl phosphate (TPhP); however, its environmental behavior and toxicological safety remain poorly defined. Here, using zebrafish larvae with TPhP as a benchmark, we systematically evaluated the developmental and neurobehavioral toxicity of HPCTP at environmentally relevant concentrations (50–5000 ng/L) from 6 to 120 h postfertilization. HPCTP showed greater bioaccumulation potential than TPhP, suggesting the risk of long-term ecological persistence. Despite lower acute toxicity, HPCTP induced pronounced developmental defects, including reduced body length and cardiac malformations. Strikingly, HPCTP and TPhP produced divergent neurobehavioral outcomes. HPCTP caused dose-dependent depression-like behaviors (hypoactivity, light-zone avoidance) through suppression of serotonin 1A (5-HT 1 A) signaling, supported by decreased htr1aa expression and serotonin levels and partially rescued by the 5-HT 1 A receptor agonist 8-OH-DPAT. By contrast, TPhP elicited anxiety-like phenotypes (hyperactivity, thigmotaxis) via CD83-dependent neuroinflammation, evidenced by decreased cd83 expression and microglial activation, which were reversed by cd83 overexpression. Taken together, these findings demonstrate that HPCTP, though marketed as a safer alternative, poses distinct developmental and neurobehavioral hazards, underscoring the urgent need for comprehensive risk evaluation prior to its widespread application.