Melatonin promotes cell cycle progression of neural stem cells subjected to manganese via Nurr1

Nan Chen; Han Zhou; Bin He; Sen Peng; Feng Ding; Qi-Hao Liu; Zhuo Ma; Wei Liu; Bin Xu

doi:10.1002/tox.24258

Melatonin promotes cell cycle progression of neural stem cells subjected to manganese via Nurr1

Environ Toxicol. 2024 Apr 2. doi: 10.1002/tox.24258. Online ahead of print.

Authors

Nan Chen¹, Han Zhou¹, Bin He¹, Sen Peng¹, Feng Ding¹, Qi-Hao Liu¹, Zhuo Ma^{1

2}, Wei Liu^{1

2}, Bin Xu^{1

2}

Affiliations

¹ Department of Environmental Health, School of Public Health, China Medical University, Shenyang, PR China.
² Key laboratory of Environmental Stress and Chronic Disease Control and Prevention (China Medical University), Ministry of Education, Shenyang, PR China.

PMID: 38563506
DOI: 10.1002/tox.24258

Abstract

Excessive exposure to manganese (Mn) through drinking water and food during pregnancy significantly heightens the likelihood of neurodevelopmental damage in offspring. Multiple studies have indicated that melatonin (Mel) may help to relieve neurodevelopmental disorders caused by Mn, but potential mechanisms underlying this effect require further exploration. Here, we utilized primary neural stem cells (NSCs) as a model to elucidate the molecular mechanism underlying the protective function of Mel on Mn-induced cell proliferation dysfunction and cycle arrest. Our results showed that Mn disrupted the cell cycle in NSCs by suppressing positive regulatory proteins (CDK2, Cyclin A, Cyclin D₁, and E2F1) and enhancing negative ones (p27^KIP1 and p57^KIP2), leading to cell proliferation dysfunction. Mel inhibited the Mn-dependent changes to these proteins and the cell cycle through nuclear receptor-related protein 1 (Nurr1), thus alleviating the proliferation dysfunction. Knockdown of Nurr1 using lentivirus-expressed shRNA in NSCs resulted in a diminished protective effect of Mel. We concluded that Mel mitigated Mn-induced proliferation dysfunction and cycle arrest in NSCs through Nurr1.

Keywords: cell cycle; manganese; melatonin; neural stem cells; nuclear receptor‐related protein 1.