Phenyl salicylate induces neurotoxicity and early Alzheimer's disease-like symptoms through ndrg1-regulated myelin damage, increasing bace1 in zebrafish.

Summary

Zebrafish embryos exposed to phenyl salicylate exhibited dose-dependent developmental and neurotoxic effects, including BBB disruption and locomotor changes. Mechanistically, phenyl salicylate downregulated ndrg1, leading to myelin damage and increased bace1 expression, yielding early Alzheimer’s disease-like phenotypes.

Key Findings

• Dose-dependent increases in mortality and malformations in zebrafish embryos exposed to 0.025–1.0 mg/L phenyl salicylate up to 144 hpf
• Adverse effects on monoaminergic neuron development, cerebral vasculature, BBB integrity, with cerebral hemorrhage and locomotor changes
• RNA-seq and validation showed ndrg1 downregulation, myelin damage, and upregulated bace1 leading to AD-like phenotypes (BBB leakage, brain bleeding, increased gfap and chrna7a)

Clinical Implications

While preclinical, the findings support cautious use of phenyl salicylate in formulations and motivate toxicological screening and exposure mitigation strategies, especially for vulnerable populations.

Limitations

• Findings are limited to a zebrafish model without mammalian validation
• Human-relevant exposure levels and long-term cognitive outcomes were not addressed

Future Directions

Validate the ndrg1–bace1 pathway in mammalian models, define human-relevant exposure thresholds, and assess behavioral/cognitive endpoints and mixture effects with co-exposures.