Bisphenol A Represses Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells through Downregulating the Expression of Insulin-like Growth Factor 1.
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.
State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China.|Center of Reproduction and Genetics, Suzhou Hospital affiliated to Nanjing Medical University, Suzhou, 215002, China.
Boxian
B
Huang
State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China.
Song
S
Ning
State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China.
Qinjing
Q
Zhang
State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China.
Aiqin
A
Chen
State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China.
Chunyan
C
Jiang
State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China.
Yugui
Y
Cui
State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China.
Jian
J
Hu
Center of Reproduction and Genetics, Suzhou Hospital affiliated to Nanjing Medical University, Suzhou, 215002, China.
Hong
H
Li
Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.
Guoping
G
Fan
State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China. ljqin@njmu.edu.cn.
Lianju
L
Qin
State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China. jyliu_nj@126.com.
Jiayin
J
Liu
D001559:Benzhydryl Compounds / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects*; D004475:Ectoderm / Q000187:drug effects / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects; D000066449:Human Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D018377:Neurotransmitter Agents / Q000378:metabolism; D010636:Phenols / Q000633:toxicity*; D055755:SOXD Transcription Factors / Q000378:metabolism; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D007334:Insulin-Like Growth Factor I; D018377:Neurotransmitter Agents; D010636:Phenols; D055755:SOXD Transcription Factors; C583557:IGF1 protein, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds
Bisphenol A; Dopaminergic neuron; Human embryonic stem cell; Neural precursor cell; Neuronal cell differentiation