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Pervasive environmental chemicals impair oligodendrocyte development

Nature Neuroscience (2024)Cite this article

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Abstract

Exposure to environmental chemicals can impair neurodevelopment, and oligodendrocytes may be particularly vulnerable, as their development extends from gestation into adulthood. However, few environmental chemicals have been assessed for potential risks to oligodendrocytes. Here, using a high-throughput developmental screen in cultured cells, we identified environmental chemicals in two classes that disrupt oligodendrocyte development through distinct mechanisms. Quaternary compounds, ubiquitous in disinfecting agents and personal care products, were potently and selectively cytotoxic to developing oligodendrocytes, whereas organophosphate flame retardants, commonly found in household items such as furniture and electronics, prematurely arrested oligodendrocyte maturation. Chemicals from each class impaired oligodendrocyte development postnatally in mice and in a human 3D organoid model of prenatal cortical development. Analysis of epidemiological data showed that adverse neurodevelopmental outcomes were associated with childhood exposure to the top organophosphate flame retardant identified by our screen. This work identifies toxicological vulnerabilities for oligodendrocyte development and highlights the need for deeper scrutiny of these compounds’ impacts on human health.

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Fig. 1: Quaternary compounds are potently cytotoxic to developing oligodendrocytes.
Fig. 2: Quaternary compounds activate the integrated stress response and are cytotoxic to human oligodendrocytes.
Fig. 3: Organophosphate flame retardants arrest oligodendrocyte maturation.
Fig. 4: TDCIPP inhibits human oligodendrocyte development and is associated with abnormal neurodevelopmental outcomes in children.

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Data availability

Primary screening results are available in Supplementary Table 1 and will be included in a future public release of the EPA ToxCast database. RNA-seq datasets generated in this study have been deposited in Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo) under accession code GSE244500. Data from the CDC’s NHANES utilized in this study is publicly available at https://wwwn.cdc.gov/Nchs/Nhanes. The mm10 genome utilized in RNA sequencing analysis is publicly available from GENCODE. Source data are provided with this paper.

Code availability

Epidemiological analyses were performed using publicly available packages and followed guidelines provided by NHANES.

References

  1. Sanmarco, L. M. et al. Identification of environmental factors that promote intestinal inflammation. Nature 611, 801–809 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wheeler, M. A. et al. Environmental control of astrocyte pathogenic activities in CNS inflammation. Cell 176, 581–596.e18 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lidsky, T. I. & Schneider, J. S. Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain 126, 5–19 (2003).

    Article  PubMed  Google Scholar 

  4. Grandjean, P. & Landrigan, P. J. Neurobehavioural effects of developmental toxicity. Lancet Neurol. 13, 330–338 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Grandjean, P. & Landrigan, P. J. Developmental neurotoxicity of industrial chemicals. Lancet 368, 2167–2178 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Landrigan, P. J. et al. Neuropsychological dysfunction in children with chronic low-level lead absorption. Lancet 1, 708–712 (1975).

    Article  CAS  PubMed  Google Scholar 

  7. Jacobson, J. L. & Jacobson, S. W. Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N. Engl. J. Med. 335, 783–789 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Li, Q. et al. Prevalence of autism spectrum disorder among children and adolescents in the United States from 2019 to 2020. JAMA Pediatr. 176, 943–945 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chung, W. et al. Trends in the prevalence and incidence of attention-deficit/hyperactivity disorder among adults and children of different racial and ethnic groups. JAMA Netw. Open 2, e1914344 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Zhou, T. et al. A hPSC-based platform to discover gene-environment interactions that impact human beta-cell and dopamine neuron survival. Nat. Commun. 9, 4815 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Caporale, N. et al. From cohorts to molecules: adverse impacts of endocrine disrupting mixtures. Science 375, eabe8244 (2022).

    Article  CAS  PubMed  Google Scholar 

  12. Bercury, K. K. & Macklin, W. B. Dynamics and mechanisms of CNS myelination. Dev. Cell 32, 447–458 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nave, K. A. Myelination and the trophic support of long axons. Nat. Rev. Neurosci. 11, 275–283 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Elitt, M. S. et al. Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease. Nature 585, 397–403 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chang, A., Tourtellotte, W. W., Rudick, R. & Trapp, B. D. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N. Engl. J. Med. 346, 165–173 (2002).

    Article  PubMed  Google Scholar 

  16. Jakel, S. et al. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature 566, 543–547 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Silbereis, J. C., Pochareddy, S., Zhu, Y., Li, M. & Sestan, N. The cellular and molecular landscapes of the developing human central nervous system. Neuron 89, 248–268 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Giedd, J. N. et al. Brain development during childhood and adolescence: a longitudinal MRI study. Nat. Neurosci. 2, 861–863 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Breinlinger, S. et al. Hunting the eagle killer: a cyanobacterial neurotoxin causes vacuolar myelinopathy. Science 371, 6536 (2021).

    Article  Google Scholar 

  20. Klose, J. et al. Neurodevelopmental toxicity assessment of flame retardants using a human DNT in vitro testing battery. Cell Biol. Toxicol. 38, 781–807 (2022).

    Article  CAS  PubMed  Google Scholar 

  21. Lager, A. M. et al. Rapid functional genetics of the oligodendrocyte lineage using pluripotent stem cells. Nat. Commun. 9, 3708 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Najm, F. J. et al. Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature 522, 216–220 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Najm, F. J. et al. Rapid and robust generation of functional oligodendrocyte progenitor cells from epiblast stem cells. Nat. Methods 8, 957–962 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Richard, A. M. et al. ToxCast chemical landscape: paving the road to 21st century toxicology. Chem. Res. Toxicol. 29, 1225–1251 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. Sommers, K. J. et al. Quaternary phosphonium compounds: an examination of non-nitrogenous cationic amphiphiles that evade disinfectant resistance. ACS Infect. Dis. 8, 387–397 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hora, P. I., Pati, S. G., McNamara, P. J. & Arnold, W. A. Increased use of quaternary ammonium compounds during the SARS-CoV-2 pandemic and beyond: consideration of environmental implications. Environ. Sci. Tech. Let. 7, 622–631 (2020).

    Article  CAS  Google Scholar 

  27. Takeda, R. et al. Antiviral effect of cetylpyridinium chloride in mouthwash on SARS-CoV-2. Sci. Rep. 12, 14050 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xiao, S., Yuan, Z. & Huang, Y. Disinfectants against SARS-CoV-2: a review. Viruses 14, 1721 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Costa-Mattioli, M. & Walter, P. The integrated stress response: from mechanism to disease. Science 368, eaat5314 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Madhavan, M. et al. Induction of myelinating oligodendrocytes in human cortical spheroids. Nat. Methods 15, 700–706 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pașca, S. P. et al. A nomenclature consensus for nervous system organoids and assembloids. Nature 609, 907–910 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Paul-Friedman, K. et al. Limited chemical structural diversity found to modulate thyroid hormone receptor in the Tox21 chemical library. Environ. Health Perspect. 127, 97009 (2019).

    Article  PubMed  Google Scholar 

  33. Liu, W. et al. Prenatal exposure to halogenated, aryl, and alkyl organophosphate esters and child neurodevelopment at two years of age. J. Hazard. Mater. 408, 124856 (2021).

    Article  CAS  PubMed  Google Scholar 

  34. Hoffman, K., Gearhart-Serna, L., Lorber, M., Webster, T. F. & Stapleton, H. M. Estimated tris(1,3-dichloro-2-propyl) phosphate exposure levels for US infants suggest potential health risks. Environ. Sci. Technol. Lett. 4, 334–338 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ciesielski, T. et al. Cadmium exposure and neurodevelopmental outcomes in U.S. children. Environ. Health Perspect. 120, 758–763 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kwon, S. & O’Neill, M. Socioeconomic and familial factors associated with gross motor skills among US children aged 3–5 years: the 2012 NHANES National Youth Fitness Survey. Int J. Environ. Res Public Health 17, 4491 (2020).

  37. Steadman, P. E. et al. Disruption of oligodendrogenesis impairs memory consolidation in adult mice. Neuron 105, 150–164.e6 (2020).

    Article  CAS  PubMed  Google Scholar 

  38. McKenzie, I. A. et al. Motor skill learning requires active central myelination. Science 346, 318–322 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xiao, L. et al. Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning. Nat. Neurosci. 19, 1210–1217 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kleinstreuer, N. C. et al. Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms. Nat. Biotechnol. 32, 583–591 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Hogberg, H. T. et al. Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model. Arch. Toxicol. 95, 207–228 (2021).

    Article  CAS  PubMed  Google Scholar 

  42. Renner, H. et al. Cell-type-specific high throughput toxicity testing in human midbrain organoids. Front Mol. Neurosci. 14, 715054 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chesnut, M., Hartung, T., Hogberg, H. & Pamies, D. Human oligodendrocytes and myelin in vitro to evaluate developmental neurotoxicity. Int. J. Mol. Sci. 22, 7929 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. About List N: Disinfectants for Coronavirus (COVID-19) (United States Environmental Protection Agency, 2023); https://www.epa.gov/coronavirus/about-list-n-disinfectants-coronavirus-covid-19-0

  45. Zheng, G., Webster, T. F. & Salamova, A. Quaternary ammonium compounds: bioaccumulation potentials in humans and levels in blood before and during the Covid-19 pandemic. Environ. Sci. Technol. 55, 14689–14698 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lin, W. & Popko, B. Endoplasmic reticulum stress in disorders of myelinating cells. Nat. Neurosci. 12, 379–385 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Li, D., Sangion, A. & Li, L. Evaluating consumer exposure to disinfecting chemicals against coronavirus disease 2019 (COVID-19) and associated health risks. Environ. Int. 145, 106108 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Herron, J. M. et al. Multiomics investigation reveals benzalkonium chloride disinfectants alter sterol and lipid homeostasis in the mouse neonatal brain. Toxicol. Sci. 171, 32–45 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Patisaul, H. B. et al. Beyond cholinesterase inhibition: developmental neurotoxicity of organophosphate ester flame retardants and plasticizers. Environ. Health Perspect. 129, 105001 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Hou, M., Zhang, B., Fu, S., Cai, Y. & Shi, Y. Penetration of organophosphate triesters and diesters across the blood–cerebrospinal fluid barrier: efficiencies, impact factors, and mechanisms. Environ. Sci. Technol. 56, 8221–8230 (2022).

    Article  CAS  PubMed  Google Scholar 

  51. Blum, A. et al. Organophosphate ester flame retardants: are they a regrettable substitution for polybrominated diphenyl ethers? Environ. Sci. Technol. Lett. 6, 638–649 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gibson, E. A. et al. Flame retardant exposure assessment: findings from a behavioral intervention study. J. Expo. Sci. Environ. Epidemiol. 29, 33–48 (2019).

    Article  CAS  PubMed  Google Scholar 

  53. Najm, F. J. et al. Isolation of epiblast stem cells from preimplantation mouse embryos. Cell Stem Cell 8, 318–325 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Najm, F. J. et al. Transcription factor-mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells. Nat. Biotechnol. 31, 426–433 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Allan, K. C. et al. Non-canonical targets of HIF1a impair oligodendrocyte progenitor cell function. Cell Stem Cell 28, 257–272.e11 (2021).

    Article  CAS  PubMed  Google Scholar 

  56. Hubler, Z. et al. Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination. Nature 560, 372–376 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bankhead, P. et al. QuPath: open source software for digital pathology image analysis. Sci. Rep. 7, 16878 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Patro, R., Duggal, G., Love, M. I., Irizarry, R. A. & Kingsford, C. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417–419 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Adamson, B. et al. A multiplexed single-cell CRISPR screening platform enables systematic dissection of the unfolded protein response. Cell 167, 1867–1882.e21 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wong, Y. L. et al. eIF2B activator prevents neurological defects caused by a chronic integrated stress response. eLife 8, e42940 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Judson, R. et al. Analysis of the effects of cell stress and cytotoxicity on in vitro assay activity across a diverse chemical and assay space. Toxicol. Sci. 153, 409 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Paul Friedman, K. et al. Utility of in vitro bioactivity as a lower bound estimate of in vivo adverse effect levels and in risk-based prioritization. Toxicol. Sci. 173, 202–225 (2020).

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by National Institutes of Health grants R35NS116842 (P.J.T.), F31NS124282 (E.F.C.), T32NS077888 (E.F.C.) and T32GM007250 (E.F.C.). B.L.L.C. is supported by an NMSS Career Transition Fellowship. M.A.S. received support from the Howard Hughes Medical Institute Hanna H. Gray Fellowship and the New York Stem Cell Foundation Druckenmiller Fellowship. Institutional support was provided by CWRU School of Medicine, and philanthropic support was generously contributed by sTF5 Care and the Long, Walter, Peterson, Goodman and Geller families. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Additional support was provided by the Small Molecule Drug Development and Light Microscopy Imaging core facilities of the CWRU Comprehensive Cancer Center (P30CA043703). The EPA provided the ToxCast screening library through an MTA with CWRU and supported the effort of EPA employees (T.J.S. and K.P.F.). We are grateful to D. Adams, A. Wynshaw-Boris, D. Kassel, K. Carr, J. Kristell, K. Allan, E. Shick, R. Ziar, A. Sterling and A. Gartley for technical assistance and/or discussion and C. Lilliehook for editorial support. This work was supported in part by the EPA and has been reviewed and approved for publication by the EPA’s Center for Computational Toxicology and Exposure. Approval for publication does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute an endorsement or recommendation for use.

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Authors and Affiliations

  1. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Erin F. Cohn, Benjamin L. L. Clayton, Mayur Madhavan, Kristin A. Lee, Sara Yacoub, Yuriy Fedorov, Marissa A. Scavuzzo & Paul J. Tesar

  2. Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA

    Katie Paul Friedman & Timothy J. Shafer

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Contributions

E.F.C., B.L.L.C., T.J.S. and P.J.T. conceived this study to screen for the effects of environmental chemicals on oligodendrocyte development. E.F.C., B.L.L.C. and P.J.T. designed and managed the experimental studies. E.F.C., B.L.L.C., K.A.L. and S.Y. performed, quantified and analyzed in vitro experiments using mouse OPCs, including primary screening and immunocytochemistry. E.F.C., K.A.L. and S.Y. performed dose–curve validations and qPCR. B.L.L.C. isolated mouse astrocytes and performed primary screening for astrocytes. E.F.C. performed RNA-seq analysis. E.F.C., K.A.L. and M.A.S. performed all in vivo experiments. K.P.F. performed ToxPrint chemotype enrichment analyses, and T.J.S. and K.P.F. guided categorization of chemical screen hits. E.F.C. designed and performed linear regression analyses using data from the NHANES. M.M. and E.F.C. performed cortical organoid experiments. Y.F. managed the chemical library and pipelined primary screening data. E.F.C. assembled all figures. E.F.C. and P.J.T. wrote the manuscript with input from all authors.

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Correspondence to Paul J. Tesar.

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Extended data

Extended Data Fig. 1 Screening a library of environmental chemicals in developing oligodendrocytes identifies cytotoxic chemicals and modulators of oligodendrocyte generation.

Representative heatmaps of one of 6 primary screening 384-well plates depicting cytotoxic compounds (red), oligodendrocyte inhibitors (blue), and drivers (yellow). Viability and percent O1+ oligodendrocytes are normalized to DMSO vehicle control (-). Thyroid hormone, a known driver of oligodendrocyte generation, is included as a positive control (+) for oligodendrocyte development. Cytotoxic hits (gray) were omitted from heatmap displaying normalized O1 percentage. b. Quantification of hits across 6 primary screening plates showing distribution of chemicals identified as cytotoxic (black), drivers (green), and inhibitors (blue). c. Top use categories for 206 validated cytotoxic chemicals and the number of chemicals belonging to each category. d. Venn diagram showing the overlap of 206 validated cytotoxic chemicals identified in the oligodendrocyte screen compared to cytotoxic hits identified in an identical screen performed in mouse astrocytes.

Source data

Extended Data Fig. 2 Quaternary compounds are selectively cytotoxic to oligodendrocytes through activation of the integrated stress response.

a-b. mPSC-derived oligodendrocytes and primary mouse oligodendrocytes were treated with 20 µM methyltrioctylammonium chloride and tributyltetradecylphosphonium chloride. a. Representative images showing DAPI and O1 immunostaining. Scale bar, 50 μm. b. Quantification of viability normalized to DMSO. Data are mean ± SD, n = 3 biological replicates. c-h. Viability of mouse PSC-derived oligodendrocytes, primary astrocytes, and fibroblasts, normalized to DMSO after treatment with quaternary compounds. Data are mean ± SEM, n = 3 biological replicates. i. IC50 concentrations of quaternary compounds in mouse oligodendrocytes, astrocytes, and fibroblasts, n = 3 biological replicates. j. Viability of oligodendrocytes normalized to DMSO cultured in the presence of methyltrioctylammonium chloride, ADEBC (C12-C14), or cetylpyridinium chloride at their respective IC75 and QVD-OPH, necrostatin-1, and ferrostatin-1. Data are mean, n = 3 biological replicates k,l. Volcano plot of differentially expressed genes in oligodendrocytes treated with 370 nM (IC75) ADEBC (C12-C14) (k) or 181 nM (IC75) cetylpyridinium chloride (l) for 4 hours. Log2FC and padj were calculated with DESeq2. Genes highlighted in red increased (padj ≤ 0.05), n = 3 biological replicates. Top 10 genes with the greatest Log2FC are labelled. m. qRT-PCR of CHOP in oligodendrocytes treated with DMSO, or top toxic compounds identified in the primary screen (not quaternary compounds). Oligodendrocytes were cultured for 4 hours in the presence of chemicals at IC75 or 20 µM if the calculated IC75 exceeded the primary screening concentration (388 nM Basic Blue 7, 20 µM 3,3’-dimethylbenzidine, 7.14 µM diisononyl cyclohexane-1,2-dicarboxylate, 1.82 µM 3,3’-dimethoxybenzidine, or 20 µM 2,4-dimethylphenol). Data are mean ± SD, n = 3 biological replicates. p-values calculated using one-way ANOVA with Dunnett post-test correction for multiple comparisons. n. qRT-PCR of CHOP in fibroblasts treated for 4 hours normalized to DMSO. Quaternary compounds were tested at their IC75 (calculated from dose response testing in fibroblasts) or 20 µM if IC75 > 20 µM (2.0 µM methyltrioctylammonium chloride, 18.8 µM ADEBC (C12-C14), 20 µM cetylpyridinium chloride). Data are mean ± SD, n = 3 biological replicates. p-values calculated using one-way ANOVA with Dunnett post-test correction for multiple comparisons. o. Oligodendrocyte viability (normalized to DMSO) after treatment with quaternary compounds (IC75) and JSH-23 or Pifithrin-µ. Data shown as mean, n = 3 biological replicates.

Source data

Extended Data Fig. 3 Quaternary compounds are toxic to mouse oligodendrocytes in vivo and in human cortical organoids.

a,b. Brain and liver concentration of methyltrioctylammonium chloride, ADEBC (C12-C14), and cetylpyridinium chloride after oral gavage (P9-P10). Data are mean ± SD, n = 3 or 1 mice (100 mg/kg/day methyltrioctylammonium chloride mice presented from n = 1 mouse due to lethality to other mice included in the study). c. Survival of mice treated with vehicle or cetylpyridinium chloride, n = 8 (vehicle), n = 10 (10 mg/kg/day), n = 11 (1 mg/kg/day). Mice were considered dead if found dead in their cage or cannibalized by dam. d-k. Mice were gavaged P5-P14 with vehicle (water) or 1 mg/kg/day cetylpyridinium chloride. Measurement of daily body (d), P14 liver (e), and P14 brain (f) weights. g. P14 cetylpyridinium chloride liver concentration, with analyte concentrations below the lower limit of detection (1 ng/mL) coded as 0. h. Representative images showing DAPI and SOX10 immunostaining. i. Quantification of oligodendrocyte lineage cell density (SOX10+ per mm2) in cortex and hippocampus of P14 mice. j. Representative images showing DAPI and NEUN immunostaining. k. Quantification of neuron density (NEUN+ per mm2) in cerebellum, cortex, and hippocampus of P14 mice. Data are mean ± SD, n = 8 or 9 mice. p-values calculated using unpaired two-tailed t test (e, f, i, k). Scale bars, 50 μm (h, j). l-o. Human cortical organoids were treated with DMSO, 94 nM methyltrioctylammonium chloride, 370 nM ADEBC (C12-C14), or 181 nM cetylpyridinium chloride (IC75). l. Representative images showing immunostaining of oligodendrocyte lineage cells (SOX10 + ), progenitors (SOX2 + ), and neurons (NeuN + ). Scale bar, 50 μm. Quantification of pre-OPC (SOX2 + SOX10+ per mm2) (m), other progenitor (SOX2 + SOX10- per mm2) (n), and neuron (NeuN+ per mm2) (o) densities in whole cortical organoids. Data are mean ± SD, n = 22, 24, 29, or 30 biological replicates (individual organoids from 4 independent batches), colored based on batch. p-values calculated using one-way ANOVA with Dunnett post-test correction for multiple comparisons.

Source data

Extended Data Fig. 4 Organophosphate flame retardants inhibit the development of mouse oligodendrocytes in vitro and in vivo.

a. Primary chemical screen of 1,531 non-cytotoxic environmental chemicals showing the effect of individual chemicals on oligodendrocyte generation, presented as percent O1+ cells normalized to the DMSO control, as shown in Fig. 2a. Dotted lines show the hit cutoffs for drivers and inhibitors. Drivers increase O1+ percentage by 22% ( > 3 SDs). Inhibitors reduce O1+ percentage by more than 50% ( > 7 SDs). Thyroid modulators are highlighted in yellow. b. IC50 concentrations, cytotoxicity median values, and use categories for three organophosphate esters identified as inhibitors of oligodendrocyte development, n = 3 biological replicates. c-d. mPSC-derived OPCs and mouse primary OPCs were treated with organophosphate flame retardants (20 μM). c. Representative images showing DAPI and O1 immunostaining, scale bar, 50 μm. d. Quantification of oligodendrocytes (O1 + ). e-f. mPSC-derived OPCs were treated with 20 µM TBPP or TMPP. Representative images (e) and quantification (f) of early (O4 + ), intermediate (O1 + ), and late (MBP + ) oligodendrocytes. Control images and TDCIPP treated oligodendrocytes are shown in Fig. 2e. Nuclei are marked with DAPI. Scale bar, 50 μm (e). Data are mean ± SEM, n = 3 biological replicates p-values calculated using two-way ANOVA (ANOVA p = ) for overall chemical differences with Dunnett’s multiple comparison test for differences within each time point (p =) (f). g-l. Mice were treated with vehicle (corn oil), 10 mg/kg/day, or 100 mg/kg/day TDCIPP. Measurement of P14 body (g), brain (h), and liver (i) weights. j. TDCIPP liver concentrations at P14, with analyte concentrations below lower limit of detection (10 ng/mL) coded as 0. k. Representative images showing DAPI, SOX10, and CC1 immunostaining Scale bar, 50 μm. l. Quantification of oligodendrocyte density (SOX10 + CC1+ per mm2) in the hippocampus and cortex of P14 mice. Data are mean ± SD from n = 8 or 9 mice (g-j, l). p-values were calculated using one-way ANOVA with Dunnett post-test correction for multiple comparisons (g-i, l).

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Extended Data Fig. 5 TDCIPP is associated with abnormal neurodevelopmental outcomes in children.

a. Representative images of human cortical organoids treated with 18.7 µM TDCIPP for 10 days, showing DAPI and NEUN immunostaining. Scale bar, 50 μm. b. Quantification of neurons (NEUM+ per mm2) in whole cortical organoids. Data are mean ± SD from n = 21 or 29 biological replicates (individual organoids from 4 independent batches). Data points are colored based on organoid batch. p-values calculated using unpaired two-tailed t test. c. Venn diagram showing co-occurrence of two neurodevelopmental outcomes in the study population. d-e. Adjusted odds ratio and associated p-values for covariates used in the logistic regression model for the neurodevelopmental outcomes requiring special education and gross motor dysfunction, n = 1564 or 1566. Significant odds ratios (p-value ≤ 0.05) are indicated by closed circles. Closed or open circles are the odds ratio and error bars indicate the 95% CI. Odds ratios and p-values were generated and visualized with the “survey” and “gtsummary” R packages. The Wald test was used to calculate p-values.

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Cohn, E.F., Clayton, B.L.L., Madhavan, M. et al. Pervasive environmental chemicals impair oligodendrocyte development. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01599-2

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