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Pervasive environmental chemicals impair oligodendrocyte development

ABSTRACT: Exposure to environmental chemicals can impair neurodevelopment. Oligodendrocytes that wrap around axons to boost neurotransmission may be particularly vulnerable to chemical toxicity as they develop throughout fetal development and into adulthood. However, few environmental chemicals have been assessed for potential risks to oligodendrocyte development. Here, we utilized a high-throughput developmental screen and human cortical brain organoids, which revealed environmental chemicals in two classes that disrupt oligodendrocyte development. Quaternary compounds, ubiquitous in disinfecting agents, hair conditioners, and fabric softeners, were potently and selectively cytotoxic to developing oligodendrocytes through activation of the integrated stress response. Organophosphate flame retardants, commonly found in household items such as furniture and electronics, were non-cytotoxic but prematurely arrested oligodendrocyte maturation. Chemicals from each of the two classes impaired human oligodendrocyte development in a 3D organoid model of prenatal cortical development. In analysis of epidemiological data from the CDC’s National Health and Nutrition Examination Survey, adverse neurodevelopmental outcomes were associated with childhood exposure to the top organophosphate flame retardant identified in our oligodendrocyte toxicity platform. Collectively, our work identifies toxicological vulnerabilities specific to oligodendrocyte development and highlights common household chemicals with high exposure risk to children that warrant deeper scrutiny for their impact on human health.

ORGANISM(S): Mus musculus

PROVIDER: GSE212190 | GEO | 2023/05/31

REPOSITORIES: GEO

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Pervasive environmental chemicals impair oligodendrocyte development

Project description: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.

2024-01-25 | GSE244500 | GEO

Tricresyl Phosphate (CAS No. 1330-78-5): 5-Day Rat Gavage Toxicogenomic Study

Project description:Tricresyl Phosphate (TCP) is an organophosphate flame retardant currently on the market and used as a replacement for phased-out polybrominated diphenyl ethers. Toxicity information on this class of chemicals is inadequate. Herein, the NTP use short-term, in vivo transcriptomic studies to inform potential points of departure for TCP.

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Triphenyl Phosphate (CAS No. 115-86-6): 5-Day Rat Gavage Toxicogenomic Study

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Isopropylated Phenol Phosphate (CAS No. 68937-41-7): 5-Day Rat Gavage Toxicogenomic Study

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2022-07-01 | GSE123432 | GEO

Isodecyl Diphenyl Phosphate (CAS No. 29761-21-5): 5-Day Rat Gavage Toxicogenomic Study

Project description:Isodecyl Diphenyl Phosphate (IDDP) is an organophosphate flame retardant currently on the market and used as a replacement for phased-out polybrominated diphenyl ethers. Toxicity information on this class of chemicals is inadequate. Herein, the NTP use short-term, in vivo transcriptomic studies to inform potential points of departure for IDDP.

2022-07-01 | GSE123431 | GEO

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Project description:2-Ethylhexyl Diphenyl Phosphate (EHDP) is an organophosphate flame retardant currently on the market and used as a replacement for phased-out polybrominated diphenyl ethers. Toxicity information on this class of chemicals is inadequate. Herein, the NTP use short-term, in vivo transcriptomic studies to inform potential points of departure for EHDP.

2022-07-01 | GSE123430 | GEO

tert-Butylphenyl Diphenyl Phosphate (CAS No. 56803-37-3): 5-Day Rat Gavage Toxicogenomic Study

Project description:tert-Butylphenyl Diphenyl Phosphate (BPDP) is an organophosphate flame retardant currently on the market and used as a replacement for phased-out polybrominated diphenyl ethers. Toxicity information on this class of chemicals is inadequate. Herein, the NTP use short-term, in vivo transcriptomic studies to inform potential points of departure for BPDP.

2022-07-01 | GSE123429 | GEO

Impacts of Gestational FireMaster 550 (FM 550) Exposure on the Neonatal Cortex are Sex Specific and Largely Attributable to the Organophosphate Esters

Project description:To investigate the potential underlying neurotoxic effect of developmental exposure to flame retardant mixture, Fire Master 550, or it brominated and organophosphate we performed gene expression profiling in PND1 rat prefrontal cortex.

2022-08-20 | GSE211430 | GEO

Comprehensive identification of proteins expressed by human oligodendroglia cell line

Project description:Oligodendrocytes are a type of neuroglia that have provide trophic support and insulation to axons in central nervous system. A proper differentiation of oligodendrocyte precursor cells is crucial for central nervous system myelination and development. Such maturation proccess can be induced in vitro by addition of 12-myristate 13-acetate (PMA) jointly to serum deprivation in oligodendrocyte precursor cell cultures. In the present work, we established a reference data set using 2D LC fractionation and ion-mobility enhanced data-independent proteomic analyses of proteins expressed by treated- and nontreated oligodendrocytes. The final dataset beyond all fractions comprised 223,531 ion peptides corresponding to 10,614 proteins groups. Our results can help futher studies using MO3.13 cells as a tool of investigation not only to oligodendrocyte maturation, also to diseases that have oligodendrocytes as key players.

2017-09-27 | PXD004696 | Pride

GDE2-dependent activation of canonical Wnt signaling in neurons regulates

Project description:Neurons and oligodendrocytes communicate to regulate oligodendrocyte development and ensure appropriate axonal myelination. Here, we show that Glycerophosphodiester phosphodiesterase 2 (GDE2) encodes a neuronal pathway that promotes oligodendrocyte maturation through the release of soluble neuronally-derived factors. Mice lacking global or neuronal GDE2 expression have reduced mature oligodendrocytes and myelin proteins but retain normal numbers of oligodendrocyte precursor cells (OPCs). WT OPCs cultured in conditioned medium (CM) from Gde2 null (Gde2KO) neurons exhibit delayed maturation, recapitulating in vivo phenotypes. Gde2KO neurons show robust reduction in canonical Wnt signaling and genetic activation of Wnt signaling in Gde2KO neurons rescues in vivo and in vitro oligodendrocyte maturation. Phosphacan, a known stimulant of OL maturation, is reduced in CM from Gde2KOneurons but is restored when Wnt signaling is activated. These studies identify GDE2 control of Wnt signaling as a neuronal pathway that signals to oligodendroglia to promote oligodendrocyte maturation.

2021-09-09 | PXD018080 | Pride

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