Bisphenol A Represses Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells through Downregulating the Expression of Insulin-like Growth Factor 1.

Abstract

Bisphenol A (BPA) is a ubiquitous compound emerging as a possible toxicant during embryonic development. Human embryonic stem cell (hESC) promises a valuable model for evaluating the effects of environmental chemicals on human prenatal development. In our study, 1μM BPA were applied to hESC-derived embryoid bodies (hEBs) and effects of BPA on neural cell differentiation were investigated. The expression level of insulin-like growth factor 1 (IGF-1) and marker genes for ectoderm, neuron progenitor cells, and dopaminergic (DA) neurons were all repressed upon BPA exposure. The population of hESC-derived neural precursor cells (NPCs) and DA neurons were decreased. Furthermore, yield of DA neuron-secreted tyrosine hydroxylase (TH) and dopamine were also reduced. When recombinant IGF-1 supplied, BPA-caused repressions were partially or completely relieved. Our further methylation microarray analysis indicated that there was a higher methylation level on the promoter of SRY-related HMG-box 5 (SOX5), a possible enhancer of IGF-1. Consistently, next quantitative polymerase chain reaction (qPCR) results confirmed that SOX5 expression was downregulated. Our investigation suggests that BPA represses DA neuron differentiation mainly through downregulating IGF-1 expression, which may attribute to the altered methylation level on the promoter of IGF-1 upstream genes. Our findings first elaborate the mechanism of IGF-1-mediated BPA effects on neuronal differentiation, which is helpful to illuminate the unique mechanism of BPA toxicity on prenatal neurodevelopment.