Brain organoids in environmental neurotoxicology: applications, mechanisms, and future perspectives

Aaseth J, Wallace D, Vejrup K, Alexander J. Methylmercury and developmental neurotoxicity: a global concern. Curr Opin Toxicol, 2020;19. https://doi.org/10.1016/j.cotox.2020.01.005

Abdulla A, Yan HN, Chen SJ, Wu LQ, Chen XS, Zhang YZ, et al. A multichannel microfluidic device for revealing the neurotoxic effects of Bisphenol S on cerebral organoids under low-dose constant exposure. Biosens Bioelectron. 2025;267:116754. https://doi.org/10.1016/j.bios.2024.116754.

Google Scholar 

Amartumur S, Nguyen H, Huynh T, Kim TS, Woo RS, Oh E, et al. Neuropathogenesis-on-chips for neurodegenerative diseases. Nat Commun. 2024;15(1):2219. https://doi.org/10.1038/s41467-024-46554-8.

Google Scholar 

Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, et al. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem. 2010;29(3):730–41. https://doi.org/10.1002/etc.34.

Google Scholar 

Bakulski KM, Seo YA, Hickman RC, Brandt D, Vadari HS, Hu H, et al. Heavy metals exposure and Alzheimer’s disease and related dementias. J Alzheimers Dis. 2020;76(4):1215–42. https://doi.org/10.3233/jad-200282.

Google Scholar 

Birey F, Andersen J, Makinson CD, Islam S, Wei W, Huber N, et al. Assembly of functionally integrated human forebrain spheroids. Nature. 2017;545(7652):54–9. https://doi.org/10.1038/nature22330.

Google Scholar 

Boda E, Rigamonti AE, Bollati V. Understanding the effects of air pollution on neurogenesis and gliogenesis in the growing and adult brain. Curr Opin Pharmacol. 2020;50:61–6. https://doi.org/10.1016/j.coph.2019.12.003.

Google Scholar 

Bu Q, Huang Y, Li M, Dai YP, Fang X, Chen K, et al. Acrylamide exposure represses neuronal differentiation, induces cell apoptosis and promotes tau hyperphosphorylation in hESC-derived 3D cerebral organoids. Food Chem Toxicol. 2020;144:111643. https://doi.org/10.1016/j.fct.2020.111643.

Google Scholar 

Caiaffa CD, Tukeman G, Delgado CZ, Ambekar YS, Mekonnen TT, Singh M, et al. Dolutegravir induces FOLR1 expression during brain organoid development. Front Mol Neurosci. 2024. https://doi.org/10.3389/fnmol.2024.1394058.

Google Scholar 

Cao Y, Ng C. Absorption, distribution, and toxicity of per- and polyfluoroalkyl substances (PFAS) in the brain: a review. Environ Sci Process Impacts. 2021;23(11):1623–40. https://doi.org/10.1039/d1em00228g.

Google Scholar 

Cao Y, Hu D, Cai C, Zhou M, Dai P, Lai Q, et al. Modeling early human cortical development and evaluating neurotoxicity with a forebrain organoid system. Environ Pollut. 2023;337:122624. https://doi.org/10.1016/j.envpol.2023.122624.

Google Scholar 

Carecho R, Marques D, Carregosa D, Masuero D, Garcia-Aloy M, Tramer F, et al. Circulating low-molecular-weight (poly)phenol metabolites in the brain: unveiling in vitro and in vivo blood-brain barrier transport. Food Funct. 2024;15(15):7812–27. https://doi.org/10.1039/d4fo01396d.

Google Scholar 

Chen XJ, Cui YL, Wang C, Shi T, Zhang RH, Xu JF, Li LQ. Toxicity of tri-ortho-cresyl phosphate to human-induced pluripotent stem cell derived human brain organoids. State Key Laboratory of NBC Protection for Civilians 2021;35(11):824–829. https://doi.org/10.3867/j.issn.1000-3002.2021.11.003

Chen S, Chen Y, Gao Y, Han B, Wang T, Dong H, et al. Toxic effects and mechanisms of nanoplastics on embryonic brain development using brain organoids model. Sci Total Environ. 2023;904:166913. https://doi.org/10.1016/j.scitotenv.2023.166913.

Google Scholar 

Chesnut M, Paschoud H, Repond C, Smirnova L, Hartung T, Zurich M-G, et al. Human IPSC-derived model to study myelin disruption. Int J Mol Sci. 2021;22(17):9473. https://doi.org/10.3390/ijms22179473.

Google Scholar 

Chhibber T, Bagchi S, Lahooti B, Verma A, Al-Ahmad A, Paul MK, et al. CNS organoids: an innovative tool for neurological disease modeling and drug neurotoxicity screening. Drug Discov Today. 2020;25(2):456–65. https://doi.org/10.1016/j.drudis.2019.11.010.

Google Scholar 

Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B. Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. Front Cell Neurosci. 2015;9:124. https://doi.org/10.3389/fncel.2015.00124.

Google Scholar 

Choi, G., Yang, H.Y., Cho, S., Kwon, D., Kim, D.W., & Ko, S.H. (2024). Brain-On-A-Chip Based on Human Pluripotent Stem Cell-Derived Neurons and Astrocytes for Neurotoxicity Testing: Communicative Astrocyte-Neuron DYnamics (CANDY) Chip. Adv Mater Technol, 9(11). https://doi.org/10.1002/admt.202400107

Dong L, Wang S, Wang X, Wang Z, Liu D, You H. Investigating the adverse outcome pathways (AOP) of neurotoxicity induced by DBDPE with a combination of in vitro and in silico approaches. J Hazard Mater. 2023;449:131021. https://doi.org/10.1016/j.jhazmat.2023.131021.

Google Scholar 

Du Z, Zang Z, Luo J, Liu T, Yang L, Cai Y, et al. Chronic exposure to (2 R,6 R)-hydroxynorketamine induces developmental neurotoxicity in hESC-derived cerebral organoids. J Hazard Mater. 2023;453:131379. https://doi.org/10.1016/j.jhazmat.2023.131379.

Google Scholar 

Enright HA, Lam D, Sebastian A, Sales AP, Cadena J, Hum NR, et al. Functional and transcriptional characterization of complex neuronal co-cultures. Sci Rep. 2020;10(1):11007. https://doi.org/10.1038/s41598-020-67691-2.

Google Scholar 

Fan P, Wang Y, Xu M, Han X, Liu Y. The application of brain organoids in assessing neural toxicity. Front Mol Neurosci. 2022. https://doi.org/10.3389/fnmol.2022.799397.

Google Scholar 

Gao X, Yuan Y, Lan Y, Lai T, Zhu L, Xu L, et al. Polystyrene nanoplastics induced retinal toxicity: size-, dose-, and developmental stage-dependent effects on human neural retina organoids. J Hazard Mater. 2025;497:139573. https://doi.org/10.1016/j.jhazmat.2025.139573.

Google Scholar 

Giandomenico SL, Sutcliffe M, Lancaster MA. Generation and long-term culture of advanced cerebral organoids for studying later stages of neural development. Nat Protoc. 2021;16(2):579–602. https://doi.org/10.1038/s41596-020-00433-w.

Google Scholar 

Gu LZ, Sun H, Chen JH. Histone deacetylases 3 deletion restrains PM2.5-induced mice lung injury by regulating NF-κB and TGF-β/Smad2/3 signaling pathways. Biomed Pharmacother. 2017;85:756–62. https://doi.org/10.1016/j.biopha.2016.11.094.

Google Scholar 

Habib A, Mateos PC, Dubey VK, Ahmad A, Acharya G, Ahluwalia BS, et al. Non-invasive quantitative acoustic imaging of intact brain organoids for structural assessment in drug discovery. Mater Today Adv. 2025;28:100651. https://doi.org/10.1016/j.mtadv.2025.100651.

Google Scholar 

Han Y, Yu Z, Chen Y, Guo X, Liu Y, Zhang H, et al. PM2.5 induces developmental neurotoxicity in cortical organoids. Environ Pollut. 2024;361:124913. https://doi.org/10.1016/j.envpol.2024.124913.

Google Scholar 

Hirano T, Ikenaka Y, Nomiyama K, Honda M, Suzuki N, Hoshi N, et al. An adverse outcome pathway-based approach to assess the neurotoxicity by combined exposure to current-use pesticides. Toxicology. 2023;500:153687. https://doi.org/10.1016/j.tox.2023.153687.

Google Scholar 

Hodgson E, Smart RC (2008) Molecular and biochemical toxicology: definition and scope. In Molecular and Biochemical Toxicology. pp. 1–4. https://doi.org/10.1002/9780470285251.ch1

Hongen T, Sakai K, Ito T, Qin X-Y, Sone H. Human-induced pluripotent stem cell-derived neural organoids as a novel in vitro platform for developmental neurotoxicity assessment. Int J Mol Sci. 2024;25(23):12523. https://doi.org/10.3390/ijms252312523.

Google Scholar 

Hu D, Cao Y, Cai C, Wang G, Zhou M, Peng L, et al. Establishment of human cerebral organoid systems to model early neural development and assess the central neurotoxicity of environmental toxins. Neural Regen Res. 2025;20(1):242–52. https://doi.org/10.4103/nrr.Nrr-d-23-00928.

Google Scholar 

Hua T, Kiran S, Li Y, Sang QA. Microplastics exposure affects neural development of human pluripotent stem cell-derived cortical spheroids. J Hazard Mater. 2022a;435:128884. https://doi.org/10.1016/j.jhazmat.2022.128884.

Google Scholar 

Hua T, Liu C, Kiran S, Gray K, Jung S, Meckes DG, et al. Phenotypic, metabolic, and biogenesis properties of human stem cell-derived cerebellar spheroids. Sci Rep. 2022b;12(1):12880. https://doi.org/10.1038/s41598-022-16970-1.

Google Scholar 

Huang Y, Dai Y, Li M, Guo L, Cao C, Huang Y, et al. Exposure to cadmium induces neuroinflammation and impairs ciliogenesis in hESC-derived 3D cerebral organoids. Sci Total Environ. 2021;797:149043. https://doi.org/10.1016/j.scitotenv.2021.149043.

Google Scholar 

Huang Y, Guo L, Cao C, Ma R, Huang Y, Zhong K, et al. Silver nanoparticles exposure induces developmental neurotoxicity in hiPSC-derived cerebral organoids. Sci Total Environ. 2022a;845:157047. https://doi.org/10.1016/j.scitotenv.2022.157047.

Google Scholar 

Huang YY, Liu X, Feng Y, Nie XL, Liu Q, Du XL, et al. Rotenone, an environmental toxin, causes abnormal methylation of the mouse brain organoid’s genome and ferroptosis. Int J Med Sci. 2022b;19(7):1184–97. https://doi.org/10.7150/ijms.74569.

Google Scholar 

Huang Y, Guo XH, Lu SY, Chen QQ, Wang ZQ, Lai L, et al. Long-term exposure to cadmium disrupts neurodevelopment in mature cerebral organoids. Sci Total Environ. 2024;912:168923. https://doi.org/10.1016/j.scitotenv.2023.168923.

Google Scholar 

Huang FF, You HZ, Tang XG, Su YT, Peng HJ, Li HZ, et al. Early-life exposure to polypropylene nanoplastics induces neurodevelopmental toxicity in mice and human iPSC-derived cerebral organoids. J Nanobiotechnol. 2025;23(1):474. https://doi.org/10.1186/s12951-025-03561-1.

Google Scholar 

Hughes S, Hessel EVS. Zebrafish and nematodes as whole organism models to measure developmental neurotoxicity. Crit Rev Toxicol. 2024;54(5):330–43. https://doi.org/10.1080/10408444.2024.2342448.

Google Scholar 

Iqubal A, Ahmed M, Ahmad S, Sahoo CR, Iqubal MK, Haque SE. Environmental neurotoxic pollutants: review. Environ Sci Pollut Res Int. 2020;27(33):41175–98. https://doi.org/10.1007/s11356-020-10539-z.

Google Scholar 

Jiang L, Huang L, Jiang W. H3K27me3-mediated epigenetic regulation in pluripotency maintenance and lineage differentiation. Cell Insight. 2024;3(4):100180. https://doi.org/10.1016/j.cellin.2024.100180.

Google Scholar 

Jo J, Xiao Y, Sun AX, Cukuroglu E, Tran HD, Göke J, et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell. 2016;19(2):248–57. https://doi.org/10.1016/j.stem.2016.07.005.

Google Scholar 

Kanton S, Boyle MJ, He Z, Santel M, Weigert A, Sanchís-Calleja F, et al. Organoid single-cell genomic atlas uncovers human-specific features of brain development. Nature. 2019;574(7778):418–22. https://doi.org/10.1038/s41586-019-1654-9.

Google Scholar 

Kilic O, Pamies D, Lavell E, Schiapparelli P, Feng Y, Hartung T, et al. Brain-on-a-chip model enables analysis of human neuronal differentiation and chemotaxis. Lab Chip. 2016;16(21):4152–62. https://doi.org/10.1039/c6lc00946h.

Google Scholar 

Kim J, Lee S, Lee J, Park JC, Kim KH, Ko JM, et al. Neurotoxicity of phenylalanine on human iPSC-derived cerebral organoids. Mol Genet Metab. 2022;136(2):132–44. https://doi.org/10.1016/j.ymgme.2022.04.005.

Google Scholar 

Kim J-i, Imaizumi K, Jurjuț O, Kelley KW, Wang D, Thete MV, et al. Human assembloid model of the ascending neural sensory pathway. Nature. 2025;642(8066):143–53. https://doi.org/10.1038/s41586-025-08808-3.

Google Scholar 

Kindberg AA, Bendriem RM, Spivak CE, Chen J, Handreck A, Lupica CR, et al. An in vitro model of human neocortical development using pluripotent stem cells: cocaine-induced cytoarchitectural alterations. Dis Model Mech. 2014;7(12):1397–405. https://doi.org/10.1242/dmm.017251.

Google Scholar 

Knight GT, Lundin BF, Iyer N, Ashton LM, Sethares WA

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