Pervasive environmental chemicals impair oligodendrocyte development

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. Mouse iPSC-derived OPCs were plated in 6-well plates coated with poly-L-ornithine (Sigma, P3655) and laminin (Sigma, L2020) in OPC medium (Fisher Scientific, 14-832-11) and allowed to attach for one hour. OPCs were incubated with methyltrioctylammonium chloride (Tox1) and tributyltetradecylphosphonium chloride (Tox2) at their approximate IC90 concentrations 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 dept of at least 20 million reads per sample.