Promotion of Lead-induced Cytotoxicity in Differentiating Neural Cells and Protective Effects of Selenium
- 1Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-Ku, Sendai, Miyagi 980-8578 Japan
- 2Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellow, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-Ku, Sendai, Miyagi 980-8578 Japan
Abstract
Lead (Pb) exposure remains a global health concern, particularly because of its adverse effects on neurodevelopment during fetal development and childhood. Early-life exposure to Pb during neuronal differentiation can impair neurodevelopment, although the underlying molecular mechanisms remain unclear. In this study, we investigated the cellular and molecular mechanisms underlying Pb-induced neurotoxicity during neural differentiation using SH-SY5Y cells. Our results demonstrated that Pb exposure caused severe injury to differentiating neural cells, leading to cell death with membrane disruption. This form of cell death was resistant to inhibitors of major regulated cell death pathways but was markedly suppressed by selenium supplementation with selenite or by the addition of selenoprotein P, a selenium transport protein. Transcriptome and protein expression analyses revealed that Pb induced endoplasmic reticulum (ER) stress responses. However, individual knockdown of selected ER-resident selenoproteins, including SELENOK, SELENOS, and SELENOT, did not abolish the protective effect of selenium, indicating that none of these proteins is individually indispensable for protection under the present experimental conditions. Peroxiredoxin 6 (PRDX6) knockout SH-SY5Y cells, which exhibit reduced selenium metabolic activity, remained responsive to the protective effect of selenium against Pb-induced cytotoxicity. Moreover, the glutathione peroxidase (GPx) mimetic ebselen also alleviated Pb toxicity under these conditions. These findings indicate that selenium protects differentiating neural cells against Pb-induced injury through mechanisms involving peroxide-reducing activity as well as additional selenium-dependent pathways. Collectively, our findings provide new insights into the molecular basis of Pb-induced neurotoxicity and support a protective role for selenium-dependent stress resistance against Pb-induced cellular injury.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s12011-026-05285-1.
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BibTeX
@article{shiina2026promotion,
title = {{Promotion of Lead-induced Cytotoxicity in Differentiating Neural Cells and Protective Effects of Selenium}},
author = {Satoru Shiina and Hayato Takashima and Hiroki Taguchi and Takayuki Kaneko and Kota Noritsugu and Takashi Toyama and Yoshiro Saito},
journal = {Biological Trace Element Research},
year = {2026},
month = aug,
doi = {10.1007/s12011-026-05285-1},
url = {https://doi.org/10.1007/s12011-026-05285-1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Promotion of Lead-induced Cytotoxicity in Differentiating Neural Cells and Protective Effects of Selenium
AU - Satoru Shiina
AU - Hayato Takashima
AU - Hiroki Taguchi
AU - Takayuki Kaneko
AU - Kota Noritsugu
AU - Takashi Toyama
AU - Yoshiro Saito
PY - 2026
DA - 2026/08/10
JO - Biological Trace Element Research
DO - 10.1007/s12011-026-05285-1
UR - https://doi.org/10.1007/s12011-026-05285-1
AB - Lead (Pb) exposure remains a global health concern, particularly because of its adverse effects on neurodevelopment during fetal development and childhood. Early-life exposure to Pb during neuronal differentiation can impair neurodevelopment, although the underlying molecular mechanisms remain unclear. In this study, we investigated the cellular and molecular mechanisms underlying Pb-induced neurotoxicity during neural differentiation using SH-SY5Y cells. Our results demonstrated that Pb exposure caused severe injury to differentiating neural cells, leading to cell death with membrane disruption. This form of cell death was resistant to inhibitors of major regulated cell death pathways but was markedly suppressed by selenium supplementation with selenite or by the addition of selenoprotein P, a selenium transport protein. Transcriptome and protein expression analyses revealed that Pb induced endoplasmic reticulum (ER) stress responses. However, individual knockdown of selected ER-resident selenoproteins, including SELENOK, SELENOS, and SELENOT, did not abolish the protective effect of selenium, indicating that none of these proteins is individually indispensable for protection under the present experimental conditions. Peroxiredoxin 6 (PRDX6) knockout SH-SY5Y cells, which exhibit reduced selenium metabolic activity, remained responsive to the protective effect of selenium against Pb-induced cytotoxicity. Moreover, the glutathione peroxidase (GPx) mimetic ebselen also alleviated Pb toxicity under these conditions. These findings indicate that selenium protects differentiating neural cells against Pb-induced injury through mechanisms involving peroxide-reducing activity as well as additional selenium-dependent pathways. Collectively, our findings provide new insights into the molecular basis of Pb-induced neurotoxicity and support a protective role for selenium-dependent stress resistance against Pb-induced cellular injury. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s12011-026-05285-1.
SN - 0163-4984
SN - 1559-0720
ER -