Exposure to 6PPD-Q induces dysfunctions of ovarian granulosa cells: Its potential role in PCOS

Hanxi Yu; Weichen Zhang; Danyun Wang; Biwei Shi; Yuhang Zhu; Weihuan Hu; Jiayi He; Jiawei Hong; Xiaolin Xu; Xiaoxiao Zheng; Wei Chen; Fangfang Wang; Fan Qu

doi:10.1016/j.jhazmat.2024.137037

Exposure to 6PPD-Q induces dysfunctions of ovarian granulosa cells: Its potential role in PCOS

J Hazard Mater. 2024 Dec 31:486:137037. doi: 10.1016/j.jhazmat.2024.137037. Online ahead of print.

Authors

Hanxi Yu¹, Weichen Zhang², Danyun Wang³, Biwei Shi³, Yuhang Zhu³, Weihuan Hu³, Jiayi He³, Jiawei Hong⁴, Xiaolin Xu⁵, Xiaoxiao Zheng⁵, Wei Chen⁶, Fangfang Wang⁷, Fan Qu⁸

Affiliations

¹ School of Medicine, Zhejiang University, Hangzhou 310003, China; Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
² Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
³ Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
⁴ School of Medicine, Zhejiang University, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China.
⁵ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; Key laboratory for accurate diagnosis and treatment of abdominal infection in Zhejiang province, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
⁶ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China; Key laboratory for accurate diagnosis and treatment of abdominal infection in Zhejiang province, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China. Electronic address: wei_chen@zju.edu.cn.
⁷ Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China. Electronic address: drwangfangfang@zju.edu.cn.
⁸ Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China. Electronic address: syqufan@zju.edu.cn.

PMID: 39764971
DOI: 10.1016/j.jhazmat.2024.137037

Abstract

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q), an environmental pollutant derived from the ozonolysis of the widely used tire rubber antioxidant 6PPD, has been found to accumulate in air, dust, and water, posing significant health risks. While its reproductive toxicity in male organisms has been established, its effects on female reproductive health remain unclear. Polycystic ovary syndrome (PCOS), a common endocrine disorder in premenopausal women, is known to be influenced by environmental pollutants. In this study, we exposed BALB/c mice intraperitoneally to 6PPD-Q, and they exhibited PCOS-like changes after 40 days, including alterations in hormone levels, estrous cycle arrest, and polycystic ovarian morphology. Then we identified significantly elevated levels of 6PPD-Q in the follicular fluid of PCOS patients compared to those with tubal infertility, and these levels were associated with clinical parameters. In the human ovarian granulosa cell line (KGN) studies, we demonstrated that 6PPD-Q induced granulosa cell apoptosis by inhibiting the PI3K/AKT/FOXO1 pathway, leading to ovarian damage and fertility decline. To our knowledge, this is the first study to report 6PPD-Q levels in human follicular fluid and its detrimental effects on female reproductive health, underscoring the need for further research on environmental impacts on PCOS.

Keywords: 6PPD-Q; Environmental exposure; Ovarian granulosa cells; PCOS.