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Mol Neurobiol. 2017 Jul;54(5):3798-3812. doi: 10.1007/s12035-016-9898-y. Epub 2016 Jun 7.

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

Author information

1
State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China.
2
Center of Reproduction and Genetics, Suzhou Hospital affiliated to Nanjing Medical University, Suzhou, 215002, China.
3
Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.
4
State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China. ljqin@njmu.edu.cn.
5
State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China. jyliu_nj@126.com.

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, 1 μM 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.

KEYWORDS:

Bisphenol A; Dopaminergic neuron; Human embryonic stem cell; Neural precursor cell; Neuronal cell differentiation

PMID:
27271280
DOI:
10.1007/s12035-016-9898-y
[Indexed for MEDLINE]

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