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28 August 2017 Iron suppresses ovarian granulosa cell proliferation and arrests cell cycle through regulating p38 mitogen-activated protein kinase/p53/p21 pathway
Mei-Jou Chen, Chia-Hong Chou, Chia-Tung Shun, Tsui-Lien Mao, Wen-Fen Wen, Chin-Der Chen, Shee-Uan Chen, Yu-Shih Yang, Hong-Nerng Ho
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Abstract

Iron is an essential nutrient that may exert toxic effects when it accumulates in tissues. Little is known regarding its effects on gonadal function. Both Fe2+ and Fe3+ could be released from iron deposition. We employed mouse nonluteinized granulosa cell for in vitro studies and human ovarian tissues for Prussian blue and immunohistochemical staining to identify the iron deposition and effect in vivo. After treatment with FeSO4-7H2O or FeCl3 in granulosa cell cultured with folliclestimulating hormone (FSH) for 48 h, we found that Fe2+ significantly suppressed FSH-induced granulosa cell proliferation and arrested the cell cycle at the G2/M phase by cell proliferation assay and flow cytometry. Fe2+ significantly increased intracellular reactive oxygen species (ROS) and ferritin levels of mouse granulosa cells. The increases in p21 and p53 messenger RNA and protein expression facilitated by Fe2+ treatment in mouse granulosa cells were significantly suppressed by separate treatments with p53 small interfering RNA and p38 mitogen-activated protein kinase (MAPK) inhibitors. An ROS inhibitor downregulated Fe2+-induced increases in p38MAPK expression in mouse granulosa cells. Quantitative analysis of immunohistochemical staining revealed that human ovarian tissue sections with positive Prussian blue staining had lower levels of proliferating cell nuclear antigen expression, but higher levels of p21, p53, and CDC25C expression than those with negative Prussian blue staining. Conclusively, Fe2+ could directly arrest the cell cycle and inhibit granulosa cell proliferation by regulating the ROS-mediated p38MAPK/p53/p21 pathway. Therefore, iron can directly affect female gonadal function.

Summary Sentence

Deposited iron on the ovary can suppress granulosa cell proliferation through arresting the cell cycle and regulating the p38MAPK/p53/p21 pathway.

© The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Mei-Jou Chen, Chia-Hong Chou, Chia-Tung Shun, Tsui-Lien Mao, Wen-Fen Wen, Chin-Der Chen, Shee-Uan Chen, Yu-Shih Yang, and Hong-Nerng Ho "Iron suppresses ovarian granulosa cell proliferation and arrests cell cycle through regulating p38 mitogen-activated protein kinase/p53/p21 pathway," Biology of Reproduction 97(3), 438-448, (28 August 2017). https://doi.org/10.1093/biolre/iox099
Received: 10 March 2017; Accepted: 25 August 2017; Published: 28 August 2017
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