4-hydroxybenzophenone exposure inhibits mouse hippocampal neural stem cell proliferation in vitro by upregulating
Yahang Lin1, Min He2, Xiaoyun Zeng1
1Department of Neurology, Wuhan Fourth Hospital/Pu'ai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, China.
Abstract:
Benzophenones are widely used in industry and commonly added in many personal care products. However, the neurotoxicity, in particular neurodevelopmental toxicity, of benzophenone family chemicals and metabolites has not been fully elucidated. Our recent mechanistic study in mice showed that early life exposure to a major benzophenone metabolite, 4-hydroxybenzophenone (4HBP), disrupted endoplasmic reticulum (ER) proteostasis and evoked inflammatory response in hippocampal neural stem cells (NSCs), leading to cognitive dysfunction. Despite so, detailed inflammatory cytokine(s) that possibly mediate this toxicity remains to be defined and validated. In this study, we confirmed that 4HBP treatment inhibited the viability and sphere growth of mouse NSCs in vitro. Importantly, re-interrogation of the transcriptomic data of NSCs treated with 4HBP identified the top upregulated genes, wherein the chemokine Cxcl1 ranked first. Immunofluorescent staining and qRT-PCR validated the robust induction of Cxcl1 on the protein and mRNA levels upon 4HBP treatment. Furthermore, siRNA-mediated knockdown of Cxcl1 transiently blocked its expression and led to enhanced NSCs viability in the presence of 4HBP. Together, these in vitro results indicated that the adverse effect of benzophenones on NSCs is mediated, at least in part, by induction of the chemokine Cxcl1.
Insights
4-hydroxybenzophenone (4HBP), a benzophenone metabolite, harms neural stem cells (NSCs) by increasing chemokine Cxcl1. Reducing Cxcl1 levels improves NSC viability, suggesting Cxcl1 mediates benzophenone neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Benzophenones are common in personal care products.
- Their neurodevelopmental toxicity is not fully understood.
- 4-hydroxybenzophenone (4HBP) exposure disrupts neural stem cell (NSC) function.
Purpose of the Study:
- Identify inflammatory factors mediating 4HBP neurotoxicity.
- Investigate the role of chemokine Cxcl1 in 4HBP's effects on NSCs.
Main Methods:
- In vitro studies on mouse NSCs treated with 4HBP.
- Transcriptomic analysis to identify upregulated genes.
- Validation using immunofluorescence, qRT-PCR, and siRNA knockdown of Cxcl1.
Main Results:
- 4HBP inhibited NSC viability and sphere growth.
- Cxcl1 was the top upregulated gene in 4HBP-treated NSCs.
- Cxcl1 knockdown partially rescued NSC viability.
Conclusions:
- 4HBP induces chemokine Cxcl1 in neural stem cells.
- Cxcl1 plays a role in the adverse effects of 4HBP on NSCs.
- This suggests Cxcl1 mediates benzophenone-induced neurotoxicity.
