Toxicogenomic analyses of the effects of BDE-47/209, TBBPA/S and TCBPA on early neural development with a human embryonic stem cell in vitro differentiation system

Flame retardants are detected in the environment worldwide, and thus pose great risks to human health. The potential effects of these chemicals on the development of the central nervous system, have recently raised public concern. In this study, to explore the toxicity of these chemicals during the early developmental stages of the human central nervous system, we induced human embryonic stem cells to differentiate into neural ectoderm in the presence of five halogenated flame retardants, BDE-47, BDE-209, TBBPA, TBBPS and TCBPA, individually or in combination. We identified a set of neural development-related biological processes that responded to these chemicals, by analyzing the whole transcriptional changes. We confirmed the RNA-seq results by qRT-PCR and found that transcription factors crucial for neural development, such as ZIC1, ZIC3, HES3, IGFBP3 and DDIS, were dysregulated by those chemicals. In addition, the five flame retardants might also influence axon growth/guidance and neuron transmission-related processes, by dysregulating genes including CNTN2, SLIT1, LRRC4C, RELN, CBLN1, CHRNB4 and GDF7. Furthermore, the chemical treatments seemed to interfere with the WNT and AHR signaling pathways. Overall, our findings revealed that BDE-209 had similar toxicity as BDE-47, whereas TBBPS and TCBPA might not be safe alternatives to TBBPA. Interestingly, we observed no obvious synergistic effects when we mixed those five flame retardants together.