Uncovering the effects of ATBC plasticizers on intracerebral hemorrhage outcomes based on network toxicology and in vitro and in vivo experimental validation

Abstract

In recent years, the incidence of intracerebral hemorrhage (ICH) has been increasing steadily. Environmental factors, such as plastic usage and chemical exposure, have been implicated in exacerbating cerebrovascular disease outcomes, including ICH. Acetyl tributyl citrate (ATBC), a non-phthalate plasticizer, is commonly used in food packaging, medical devices, and children's toys. Due to its high leaching potential from plastic materials, human exposure to ATBC has become increasingly prevalent. Although previous studies have generally reported ATBC as safe for human health, they have primarily focused on high-dose exposures, with limited evidence regarding the safety of environmentally relevant concentrations. This study investigated the effects of medium- to long-term exposure to environmentally relevant concentrations of ATBC. The results showed that ATBC exposure contributed to hematoma enlargement, induced neuronal cell death, and severely impaired intestinal barrier function in ICH mice. ATBC pretreatment reduced neurofilament and axon protein expression and activated the SRC-STAT3-MMPs pathway in BV2 cells in vitro. Based on these medium- to long-term in vivo and in vitro findings, ATBC may be a potential environmental risk factor that worsens the prognosis of ICH. The use of ATBC in consumer products warrants careful reevaluation.

Keywords: ATBC; ICH; Molecular docking; Network toxicology; SRC-STAT3 pathway.