Pervasive environmental chemicals impair oligodendrocyte development
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. Overall design: OPCs were plated in 6-well plates coated with poly-L-ornithine (Sigma, P3655) and laminin (Sigma, L2020) in differentiation permissive media and allowed to attach for one hour. OPCs were incubated with vehicle (DMSO), cetylpyridinium chloride (Tox1), C12-C14-Alkyl(ethylbenzyl)dimethylammonium chloride (Tox2), or methyltrioctylammonium chloride (Tox3), at their respective IC75 for 4 hours. OPCs were then lysed in TRIzol (Invitrogen, 15596018) and RNA was extracted by phenol-chloroform extraction and purified using the Rneasy Mini Kit (Qiagen, 74104). Samples were sent to Novogene for library preparation and mRNA sequencing. Libraries were generated according to protocols from the NEBNext Poly(A) mRNA Magnetic Isolation Module (NEB, E7490L) and NEBNext Ultra RNA Library Prep Kit for Illumina (NEB, E7530L) and then evenly pooled and sequenced on the Illumina NovaSeq with 150bp paired-end reads and a read depth of at least 20 million reads per sample.