In a recent study published in the journal Nature Neuroscience, researchers in the United States pinpointed and evaluated environmental chemicals that hinder oligodendrocyte development through varied mechanisms, assessing their neurodevelopmental impacts.
Study: Pervasive environmental chemicals impair oligodendrocyte development. Image Credit: Lightspring / Shutterstock
Background
Human exposure to environmental chemicals, especially during the critical developmental stages of children's central nervous systems, raises significant health concerns. Substances like methylmercury, lead, and polychlorinated biphenyls are linked to disrupting brain development, potentially contributing to the increasing prevalence of neurodevelopmental disorders such as autism and Attention-Deficit/Hyperactivity Disorder (ADHD). These trends suggest that environmental factors play a critical role beyond genetics. Oligodendrocytes, vital for brain functionality through myelination and neuronal support, are particularly susceptible to these chemicals from fetal development into adolescence. Despite their significance, limited research has focused on the impact of environmental toxins on oligodendrocytes. This gap highlights the need for further investigation into how these chemicals affect oligodendrocyte development and identifying ways to counteract their detrimental effects on neurodevelopment.
About the study
The present study adhered to ethical standards set by the International Society for Stem Cell Research and the National Institutes of Health, receiving approval from the Case Western Reserve University Institutional Animal Care and Use Committee. Mouse oligodendrocyte precursor cells (OPCs) were cultured from induced pluripotent stem cells (iPSCs), following established protocols that involved removing iPSCs from a feeder layer, dissociating them, and then cultivating them in a medium conducive to OPC expansion and maturation. The culture medium was switched on the tenth day to promote OPC development, utilizing a specific combination of supplements to enrich OPC populations. Additionally, primary mouse OPCs and astrocytes were derived from dissected mouse brain tissue, with the cells undergoing culture in specially prepared media to encourage the growth of OPCs and astrocytes, respectively.
Human cortical organoids were generated from embryonic stem cells and iPSCs, following rigorous stem cell research guidelines. These organoids were cultured in a medium optimized for OPC expansion and differentiation, incorporating various growth factors and supplements. Chemical screening on OPCs utilized the United States Environmental Protection Agency (US EPA) Toxicity Forecaster chemical library to identify compounds that disrupt OPC development.
Various methods, including immunocytochemistry, high-content imaging, and cell viability assays, were employed to assess the impact of chemicals on OPCs. Additionally, the study explored the effects of specific quaternary compounds on cell viability, employing a range of experimental setups across different cell types to understand the compounds' toxicity profiles.
Study results
The present study developed a high-throughput screening method to assess the impact of environmental chemicals on the development of mouse pluripotent stem cells (mPSCs)- derived OPCs into oligodendrocytes. Among the 1,823 chemicals screened, a selection was found to either be cytotoxic to developing oligodendrocytes or impede their generation without inducing cytotoxicity. The screening revealed that a majority of the chemicals had no significant effect on oligodendrocyte development or viability, yet 292 were identified as cytotoxic and 47 as inhibitors of oligodendrocyte generation.
Further investigation using the MTS assay, which measures metabolic activity as an indicator of cell viability, validated the cytotoxic effects of certain chemicals. Comparison of cytotoxicity profiles across different cell types, including mouse astrocytes and data from the US EPA, identified quaternary compounds as selectively cytotoxic to oligodendrocytes. These compounds, characterized by a central nitrogen with four alkyl groups, demonstrated a specific toxicological sensitivity in developing oligodendrocytes. The study also explored the activation of the integrated stress response (ISR) as a potential mechanism for the cytotoxicity induced by quaternary compounds.
Quaternary compounds were also tested for their ability to cross the blood-brain barrier and were found to be present in brain tissue at nanomolar concentrations following administration to mice. Furthermore, the study extended to human pluripotent stem cell-derived regionalized neural organoid models, confirming that quaternary compounds could disrupt human oligodendrocyte development, reducing the density of SOX10+ OPCs and oligodendrocytes.
Additionally, the screening identified organophosphate flame retardants as inhibitors of oligodendrocyte development. These compounds were shown to arrest the progression of early to intermediate and mature oligodendrocytes. The study's findings were extended to in vivo and in vitro models of human brain development, demonstrating that exposure to organophosphate flame retardants, particularly Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), significantly reduced the number of SOX10+CC1+ oligodendrocytes in both mouse and human models.
Lastly, the study utilized data from the National Health and Nutrition Examination Survey (NHANES) to investigate associations between exposure to organophosphate flame retardants and neurodevelopmental outcomes in children. High levels of urinary Bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), a metabolite indicative of TDCIPP exposure, were associated with an increased likelihood of special education needs and gross motor dysfunction, suggesting a strong link between organophosphate flame retardant exposure and adverse neurodevelopmental outcomes.
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