Sp1-activated FGFR2 is involved in early-life exposure to nickel-induced craniosynostosis by regulating the ERK1/2 signaling pathway

• Published in: Environment international Vol. 184; p. 108477
• Main Authors: Weng, Zhenkun, Xu, Cheng, Chen, Xiu, Yan, Qing, Fu, Zuqiang, Jiao, Jian, Xu, Jin, Liu, Qian, Wang, Dongmei, Liang, Jingjia, Li, Wenxiang, Gu, Aihua
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.02.2024; Elsevier
• Subjects: Animals; Craniosynostoses - genetics; Craniosynostosis; DNA methylation; ERK1/2 signaling; Female; FGFR2; Humans; MAP Kinase Signaling System - physiology; Mice; Nickel; Nickel - toxicity; Osteogenesis; Pregnancy; Receptor, Fibroblast Growth Factor, Type 2; Signal Transduction; DNA methylation; Nickel; Craniosynostosis; FGFR2; ERK1/2 signaling
• ISSN: 0160-4120; 1873-6750
• DOI: 10.1016/j.envint.2024.108477

[Display omitted] •FGFR2-mediated ERK1/2 activation is involved in nickel-induced craniosynostosis.•Nickel upregulates FGFR2 via promoter hypomethylation and transcription factor Sp1.•Administration of AZD4547 effectively alleviates nickel-induced craniosynostosis.•FGFR2 plays mediating role in nickel-induced craniosynostosis in population study. Nickel, a common environmental hazard, is a risk factor for craniosynostosis. However, the underlying biological mechanism remains unclear. Here, we found that early-life nickel exposure induced craniosynostosis in mice. In vitro, nickel promoted the osteogenic differentiation of human mesenchymal stem cells (hMSCs), and its osteogenic ability in vivo was confirmed by an ectopic osteogenesis model. Further mRNA sequencing showed that ERK1/2 signaling and FGFR2 were aberrantly activated. FGFR2 was identified as a key regulator of ERK1/2 signaling. By promoter methylation prediction and methylation-specific PCR (MSP) assays, we found that nickel induced hypomethylation in the promoter of FGFR2, which increased its binding affinity to the transcription factor Sp1. During pregnancy and postnatal stages, AZD4547 rescued nickel-induced craniosynostosis by inhibiting FGFR2 and ERK1/2. Compared with normal individuals, nickel levels were increased in the serum of individuals with craniosynostosis. Further logistic and RCS analyses showed that nickel was an independent risk factor for craniosynostosis with a nonlinear correlation. Mediated analysis showed that FGFR2 mediated 30.13% of the association between nickel and craniosynostosis risk. Collectively, we demonstrate that early-life nickel exposure triggers the hypomethylation of FGFR2 and its binding to Sp1, thereby promoting the osteogenic differentiation of hMSCs by ERK1/2 signaling, leading to craniosynostosis.