Sp1-activated FGFR2 is involved in early-life exposure to nickel-induced craniosynostosis by regulating the ERK1/2 signaling pathway
Open accessAbstract
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.
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Exposure to metals such as tin, nickel, and chromium may represent a risk throughout pregnancy due to their effects on osteoblasts.
“In contrast, exposure to metals such as tin, nickel, and chromium may represent a risk throughout pregnancy due to their effects on osteoblasts [114].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [114]
These exposures can alter FGFR2 expression by decreasing methylation in the FGFR2 regulatory region and enhancing access to the Sp1 transcription factor, leading to abnormal FGFR2 upregulation and premature osteogenic differentiation.
“These exposures can alter FGFR2 expression by decreasing methylation in the FGFR2 regulatory region and enhancing access to the Sp1 transcription factor, leading to abnormal FGFR2 upregulation and premature osteogenic differentiation [114].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [114]
Maternal occupation can increase exposure of metals and polycyclic aromatic hydrocarbons (PAHs) to the foetus.
“Another important factor that can influence skull growth and correct bone differentiation is maternal occupation, which can increase the exposure of metals [114, 118] and polycyclic aromatic hydrocarbons (PAHs) to the foetus [89].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [114]
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- Authors
- Weng, Z., Xu, C., Chen, X., Yan, Q., Fu, Z., Jiao, J., Xu, J., Liu, Q., Wang, D., Liang, J., Li, W., & Gu, A.
- Affiliations
- Changzhou No.2 People's Hospital (CN)
- State Key Laboratory of Reproductive Medicine (CN)
- Nanjing Children's Hospital (CN)
- Corresponding author
- Gu, Aihua
- Venue
- Environment International
- Publisher
- Elsevier BV
- Published
- 2024-02
- Volume
- 184
- Pages
- 108477
- ISSN
- 0160-4120 (ISSN-L)
- OpenAlex
- W4391542868
- Cited by
- 5
- References
- 60
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Environment International (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (91839102, 81900281, 91943301)
- National Key Research and Development Program of China
- Nanjing Medical University (2023YFC39005202, 82330104, 82273657, 2019YFA0802701, U21A20340, CMCP202306, CMCP202309)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- nickel exposure, craniosynostosis, FGFR2, Sp1, ERK signaling, promoter methylation, osteogenic differentiation, mesenchymal stem cells, AZD4547, early life exposure, pregnancy, postnatal development
- MeSH terms
- Animals, Craniosynostoses, Female, Humans, Nickel, Osteogenesis, Pregnancy, Signal Transduction, MAP Kinase Signaling System, Mice, Receptor, Fibroblast Growth Factor, Type 2
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