Gestational dibutyl phthalate exposure impairs primordial folliculogenesis in mice through autophagy activation and NOTCH2 signal interruption

作者全名："Zhang, Yan; Wan, Yiji; Mu, Xinyi; Gao, Rufei; Geng, Yanqing; Chen, Xuemei; Li, Fangfang; He, Junlin"

作者地址："[Zhang, Yan; Wan, Yiji; Gao, Rufei; Chen, Xuemei; Li, Fangfang; He, Junlin] Chongqing Med Univ, Sch Publ Hlth, Dept Hlth Toxicol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China; [Zhang, Yan; Wan, Yiji; Mu, Xinyi; Gao, Rufei; Geng, Yanqing; Chen, Xuemei; Li, Fangfang; He, Junlin] Chongqing Med Univ, Joint Int Res Lab Reprod & Dev, Chongqing 400016, Peoples R China; [Mu, Xinyi; Geng, Yanqing] Chongqing Med Univ, Sch Basic Med, Chongqing 400016, Peoples R China"

通信作者："He, JL (通讯作者)，Chongqing Med Univ, Sch Publ Hlth, Dept Hlth Toxicol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China."

来源：FOOD AND CHEMICAL TOXICOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001020367100001

JCR分区：Q1

影响因子：3.9

年份：2023

卷号：178

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Dibutyl phthalate; Primordial folliculogenesis; Autophagy; NOTCH2; Melatonin; Fertility

摘要："Female reproductive lifespan is largely determined by the size of the primordial follicle pool, which is established in early life. Dibutyl phthalate (DBP), a popular plasticiser, is a known environmental endocrine disruptor that poses a potential threat to reproductive health. However, DBP impact on early oogenesis has been rarely re-ported. In this study, maternal exposure to DBP in gestation disrupted germ-cell cyst breakdown and primordial follicle assembly in foetal ovary, impairing female fertility in adulthood. Subsequently, altered autophagic flux with autophagosome accumulation was observed in DBP-exposed ovaries carrying CAG-RFP-EGFP-LC3 reporter genes, whereas autophagy inhibition by 3-methyladenine attenuated the impact of DBP on primordial folli-culogenesis. Moreover, DBP exposure reduced the expression of NOTCH2 intracellular domain (NICD2) and decreased interactions between NICD2 and Beclin-l. NICD2 was observed within the autophagosomes in DBP-exposed ovaries. Furthermore, NICD2 overexpression partially restored primordial folliculogenesis. Further-more, melatonin significantly relieved oxidative stress, decreased autophagy, and restored NOTCH2 signalling, consequently reversing the effect on folliculogenesis. Therefore, this study demonstrated that gestational DBP exposure disrupts primordial folliculogenesis by inducing autophagy, which targets NOTCH2 signalling, and this impact has long-term consequences on fertility in adulthood, strengthening the potential contribution of envi-ronmental chemicals to the development of ovarian dysfunctional diseases."

基金机构：National Natural Sci-ence Foundation of China [32070851]; Postdoctoral Science Foundation of Chongqing [CSTB2022NSCQ-BHX004]; Special Funding for Postdoctoral Research Project of Chongqing [2021XM3054]; Special Professorship Project of Chongqing Medical University [2021-215]

基金资助正文："Acknowledgments This study was supported by grants from the National Natural Sci-ence Foundation of China (Grant No. 32070851) , and the Postdoctoral Science Foundation of Chongqing (Grant No. CSTB2022NSCQ-BHX004) , and the Special Funding for Postdoctoral Research Project of Chongqing (Grant No. 2021XM3054) , and the Special Professorship Project of Chongqing Medical University (2021-215) ."