Acetyl tributyl citrate induces neuronal ferroptosis through ATM-associated disruption of iron and redox homeostasis.

Abstract

BACKGROUND: Acetyl tributyl citrate (ATBC) is widely used as a non-phthalate plasticizer, raising concerns about its potential health effects. Although emerging evidence suggests that ATBC may adversely affect the nervous system, the underlying mechanisms remain poorly understood. Given the critical role of ferroptosis in neuronal injury, this study investigated whether ferroptosis contributes to ATBC-induced neuronal injury and explored the potential involvement of ataxia-telangiectasia mutated (ATM) in this process. METHODS: Network toxicology was first employed to identify potential targets linking ATBC exposure, neuronal injury, and ferroptosis, followed by protein-protein interaction analysis, functional enrichment, and molecular docking. The predicted mechanisms were subsequently evaluated in ATBC-exposed HT22 cells through ferroptosis-related molecular, oxidative, and ultrastructural assessments, with ATM silencing used to examine its regulatory role. An ATBC-exposed mouse model was further employed to validate ferroptosis-related alterations in hippocampal tissue. RESULTS: Network analysis identified ATM as a central candidate target, while molecular docking and molecular dynamics simulation predicted a potential ATBC-ATM interaction. ATBC exposure reduced HT22 cell viability, increased ATM, TFRC, Keap1 and PTGS2 expression, decreased SLC7A11, SLC40A1, NRF2 and GPX4 expression, disrupted iron and redox homeostasis, and induced ferroptosis-associated mitochondrial alterations. ATM knockdown partially reversed these changes. Consistently, ATBC exposure induced similar molecular, redox, and mitochondrial alterations in the mouse hippocampus. CONCLUSIONS: These findings support the involvement of ferroptosis in ATBC-induced hippocampal neuronal injury and suggest ATM as an important mediator of this process. This study provides mechanistic insight into the potential neurological effects of ATBC and identifies ATM-associated ferroptosis as a potential mechanism underlying ATBC-induced neuronal injury.

Key Findings

• ATBC exposure induces neuronal ferroptosis by disrupting iron and redox homeostasis.
• ATM is identified as a central mediator in ATBC-induced ferroptosis and neuronal injury.
• ATBC exposure decreases NRF2 and GPX4 expression while increasing ATM, TFRC, Keap1, and PTGS2 expression, contributing to ferroptosis.
• ATM knockdown partially reverses ferroptosis-related molecular and mitochondrial alterations caused by ATBC.
• Similar ferroptosis-related changes were observed in the hippocampus of ATBC-exposed mice.

Clinical Significance

Citation

Luo Xiao-Ting, Li Yan, Xu Li-Minget al.. Acetyl tributyl citrate induces neuronal ferroptosis through ATM-associated disruption of iron and redox homeostasis. Ecotoxicology and environmental safety. 2026-Nov-06.