Advanced understanding of the neurotoxicity of brominated flame retardants: Integrating human neural organoids with multi-omics

The developing nervous system is susceptible to environmental chemical exposure. Polybrominated diphenyl ethers (PBDEs) are brominated flame retardants that can induce neurodevelopmental impairments and neural dysfunction in animals. To investigate the toxicity of PBDEs to the human developing nervous system, neural organoid models, such as human cortical organoids (hCOs) and human retinal organoids (hROs), were established and exposed to BDE-47, BDE-209, and BDE-MIX (BDE-47/-209). Exposure to PBDEs caused morphological changes in both hCOs and hROs, as evidenced by decreased organoid size and thinning of the neural epithelium. Exposure to BDE-MIX exerted stronger effects on organoid sizes than BDE-47 or BDE-209 exposure alone. Compared to the control group, PBDE exposure significantly reduced cell proliferation (Ki67⁺ cells) and induced neuronal apoptosis (TUNEL⁺ cells). Moreover, PBDE exposure disrupted cell differentiation and neuronal distribution. PBDEs exerted comparable neurotoxic effects on both cortical and retinal development. Toxic effects of PBDEs depended on the exposure dose and the developmental stage at which exposure occurred. mRNA profiling of hCOs and hROs demonstrated that PBDE-induced common neurotoxicity may be mediated by disrupting anatomical structure morphogenesis, neurogenesis, the generation of neurons, and axon guidance. miRNA profiling of BDE-exposed organoids showed that PBDE exposure was closely associated with the neuron apoptotic process and neuron death. The integration analysis of mRNA-miRNA showed that hsa-let-7a-3p, hsa-let-7a-5p, and hsa-let-7b-5p play vital roles in PBDE-induced neurotoxicity. This study is expected to provide additional evidence to substantiate the neurotoxicity of PBDEs to humans based on neural organoids.