Using a Multi-Stage hESC Model to Characterize BDE-47 Toxicity During Neurogenesis
| Autor: | Charles J Fernandez, Helia Seifikar, Yvonne Kim, Joshua F. Robinson, Nicomedes Abello, Nicholas Larocque, Ibrahim Khatib, Hao Chen |
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| Rok vydání: | 2019 |
| Předmět: |
Neurotoxicology
polybrominated diphenyl ethers Pediatric Research Initiative methylome Biology Regenerative Medicine Toxicology Transcriptome Precursor cell neurotoxicity 2.2 Factors relating to the physical environment human Stem Cell Research - Embryonic - Human Aetiology reproductive and urinary physiology Pediatric Neurogenesis Neurosciences in vitro Pharmacology and Pharmaceutical Sciences embryonic stem cells Cell cycle Stem Cell Research alternative model Embryonic stem cell Cell biology neurogenesis endocrine disruptors Neurological Toxicity DNA methylation transcriptome Neural development |
| Zdroj: | Toxicol Sci Toxicological sciences : an official journal of the Society of Toxicology, vol 171, iss 1 |
| ISSN: | 1096-0929 1096-6080 |
| DOI: | 10.1093/toxsci/kfz136 |
| Popis: | Although the ramifications associated with polybrominated diphenyl ethers (PBDEs) exposures during human pregnancy have yet to be determined, increasing evidence in humans and animal models suggests that these compounds cause neurodevelopmental toxicity. Human embryonic stem cells (hESCs) models can be used to study the effects of environmental chemicals throughout the successive stages of neuronal development. Here, using a hESC differentiation model, we investigated the effects of common PBDE congeners (BDE-47 or -99) on the successive stages of early neuronal development. First, we determined the points of vulnerability to PBDEs across 4 stages of in vitro neural development by using assays to assess for cytotoxicity. Differentiated neural progenitors were identified to be more sensitive to PBDEs than their less differentiated counterparts. In follow-up investigations, we observed BDE-47 to inhibit functional processes critical for neurogenesis (eg, proliferation, expansion) in hESC-derived neural precursor cells (NPCs) at sub-lethal concentrations. Finally, to determine the mechanism(s) underlying PBDE-toxicity, we conducted global transcriptomic and methylomic analyses of BDE-47. We identified 589 genes to be differentially expressed due to BDE-47 exposure, including molecules involved in oxidative stress mediation, cell cycle, hormone signaling, steroid metabolism, and neurodevelopmental pathways. In parallel analyses, we identified a broad significant increase in CpG methylation. In summary our results suggest, on a cellular level, PBDEs induce human neurodevelopmental toxicity in a concentration-dependent manner and sensitivity to these compounds is dependent on the developmental stage of exposure. Proposed mRNA and methylomic perturbations may underlie toxicity in early embryonic neuronal populations. |
| Databáze: | OpenAIRE |
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