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

Phenyl salicylate, an important industrial raw material, is widely used in plastics, cosmetics, and pharmaceuticals. However, little is known about its neurotoxicity on wildlife. Here, we exposed zebrafish embryos at 4 hours post-fertilization (hpf) to 0.025, 0.05, 0.1, 0.25, 0.5, and 1.0 mg/L of phenyl salicylate up to 144 hpf and found its developmental- and neuro-toxicity. Specifically, a dose-dependent increase in mortality and malformation in zebrafish were revealed. Phenyl salicylate also adversely affected the development of monoaminergic neurons, cerebral blood vessels, and the blood-brain barrier (BBB), as well as induced cerebral hemorrhages and locomotion change. RNA-sequencing results combined with verification data showed that phenyl salicylate downregulated the expression of the N-myc downstream regulated gene-1 (ndrg1), caused myelin damage in zebrafish, and then increased expression of beta-secretase 1 (bace1), which ultimately led to early Alzheimer's disease (AD)-like symptoms, including BBB leakage, bleeding in the brain, and upregulation of the glial fibrillary acidic protein gene (gfap) and cholinergic system-related gene (chrna7a). In conclusion, phenyl salicylate exposure triggered developmental toxicity and neurotoxicity in zebrafish, which has a potential risk for the development of AD. Given the effects of phenyl salicylate exposure to ecosystem, the safety usage limit should be treated with caution.