Integrated multi-level analysis reveals the neurotoxic mechanisms of BDE-209 in zebrafish brain

Abstract

Decabromodiphenyl ether (BDE-209), the most widely used polybrominated diphenyl ether (PBDE), remains environmentally persistent and bioaccumulative, yet its comprehensive neurotoxic mechanisms in aquatic ecosystems remain unresolved. Here, we integrated single-cell RNA sequencing (scRNA-seq) with multi-level analysis to investigate the neurotoxicity of BDE-209 in zebrafish brain. Zebrafish exposed to environmentally relevant and high concentrations of BDE-209 for 21 d did not show visible morphological changes but exhibited significant biochemical alterations, including decreased superoxide dismutase, increased lipid peroxidation, and upregulated pro-inflammatory cytokines, indicating sublethal neurotoxicity in the absence of acute lethality and overt morphological alterations. Histological staining revealed neuronal damage and apoptosis, corroborating the biochemically observed oxidative stress and inflammatory responses. The scRNA-seq results further revealed cell-type–specific transcriptional changes in macrophages, natural killer T cells, excitatory neurons, and inhibitory neurons, involving pathways related to oxidation (PPAR signaling pathway), immune activation (Toll-like, NOD-like, RIG-I-like, and C-type lectin receptor pathways), and neurotransmission (endocytosis and efferocytosis pathways). In addition, network analysis identified central genes that mediate these processes. Our results provide the first cellular- and molecular-resolution evidence that BDE-209 induces an oxidation–immune–neurotransmission neurotoxic cascade in zebrafish brain. These findings will advance our mechanistic understanding of the toxicity of PBDEs in aquatic ecosystems and provide new insights into environmental risk assessment and effective management of persistent flame retardants.

Graphical abstract

Keywords

Polybrominated diphenyl ethers / Decabromodiphenyl ether / Neurotoxicity / Zebrafish / Brain / scRNA-seq

Highlight

	● Multi-level analyses reveal BDE-209 neurotoxicity in zebrafish brains.
	● scRNA-seq identifies cell-type-specific brain responses to BDE-209.
	● BDE-209 triggers an oxidation-immune-neurotransmission toxicity cascade.
	● Macrophages, NKT cells, and neurons show distinct responses to BDE-209.
	● Our findings inform PBDE risk assessment and environmental management.

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