Long-term 4-nonylphenol exposure drives cervical cell malignancy through MAPK-mediated ferroptosis inhibition

Xing Zhang; Wenjing Yan; Xue Chen; Xiuting Li; Bingjia Yu; Yan Zhang; Bo Ding; Jing Hu; Haohan Liu; Yamei Nie; Fengying Liu; Yun Zheng; Yiran Lu; Jin Wang; Shizhi Wang

doi:10.1016/j.jhazmat.2024.134371

Long-term 4-nonylphenol exposure drives cervical cell malignancy through MAPK-mediated ferroptosis inhibition

J Hazard Mater. 2024 Apr 21:471:134371. doi: 10.1016/j.jhazmat.2024.134371. Online ahead of print.

Authors

Xing Zhang¹, Wenjing Yan¹, Xue Chen¹, Xiuting Li², Bingjia Yu², Yan Zhang³, Bo Ding⁴, Jing Hu¹, Haohan Liu¹, Yamei Nie¹, Fengying Liu¹, Yun Zheng¹, Yiran Lu¹, Jin Wang¹, Shizhi Wang⁵

Affiliations

¹ Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China.
² School of Health Management and Basic Science, Jiangsu Health Vocational College, Nanjing, China.
³ School of Medicine, Shihezi University, Xinjiang, China.
⁴ Department of Gynecology and Obstetrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
⁵ Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China. Electronic address: shizhiwang2009@seu.edu.cn.

PMID: 38657513
DOI: 10.1016/j.jhazmat.2024.134371

Abstract

4-NP (4-nonylphenol), a prevalent environmental endocrine disruptor with estrogenic properties, is commonly detected in drinking water and food sources. It poses a significant risk of endocrine disruption, thereby influencing the onset and progression of diverse diseases, including tumorigenesis. However, its specific impact on cervical cancer remains to be fully elucidated. Our study focused on the biological effects of sustained exposure to low-dose 4-NP on human normal cervical epithelial cells (HcerEpic). After a continuous 30-week exposure to 4-NP, the treated cells exhibited a significant malignant transformation, whereas the solvent control group showed limited malignant phenotypes. Subsequent analyses of the metabolomic profiles of the transformed cells unveiled marked irregularities in glutathione metabolism and unsaturated fatty acid metabolism. Analyses of transcriptomic profiles revealed significant activation of the MAPK signaling pathway and suppression of ferroptosis processes in these cells. Furthermore, the expression of MT2A was significantly upregulated following 4-NP exposure. Knockdown of MT2A restored the aberrant activation of the MAPK signaling pathway, elevated antioxidant capacity, ferroptosis inhibition, and ultimately the development of malignant phenotypes that induced by 4-NP in the transformed cells. Mechanistically, MT2A increased cellular antioxidant capabilities and facilitated the removal of toxic iron ions by enhancing the phosphorylation of ERK1/2 and JNK MAPK pathways. The administration of activators and inhibitors of the MAPK pathway confirmed that the MAPK pathway mediated the 4-NP-induced suppression of ferroptosis and, ultimately, the malignant transformation of cervical epithelial cells. Overall, our findings elucidated a dynamic molecular transformation induced by prolonged exposure to 4-NP, and delineated comprehensive biological perspectives underlying 4-NP-induced cervical carcinogenesis. This offers novel theoretical underpinnings for the assessment of the carcinogenic risks associated with 4-NP.

Keywords: 4-nonylphenol; Cervical cancer; Ferroptosis; MT2A; Malignant transformation.