Ti₃C₂ nanosheet-induced autophagy derails ovarian functions

作者全名：Yang, Limei; He, Zhiting; Hu, Le; Tang, Hongyu; Geng, Yanqing; Tan, Qiaoyan; Zhang, Yue; Wen, Yixian; Wu, Wei; Gu, Huayan; Liu, Xueqing

作者地址：[Yang, Limei; Tan, Qiaoyan; Gu, Huayan; Liu, Xueqing] Chongqing Med Univ, Dept Obstet & Gynecol, Women & Childrens Hosp, 120 Longshan Rd, Chongqing 401147, Peoples R China; [Yang, Limei; Tan, Qiaoyan; Zhang, Yue; Gu, Huayan] Chongqing Municipal Hlth Commiss Key Lab Perinatal, Chongqing 400016, Peoples R China; [He, Zhiting; Geng, Yanqing; Wen, Yixian; Liu, Xueqing] Chongqing Med Univ, Sch Publ Hlth & Management, Dept Reprod Biol, Joint Int Res Lab Reprod & Dev, 1 Yixueyuan Rd,Box 197, Chongqing 400016, Peoples R China; [Hu, Le] Lanzhou Univ, Gansu Prov Clin Res Ctr Gynecol Oncol, Dept Obstet & Gynecol, Hosp 1, Lanzhou 730000, Gansu, Peoples R China; [Tang, Hongyu] Chongqing Med Univ, Dept Pediat, Women & Childrens Hosp, Chongqing 401147, Peoples R China; [Zhang, Yue] Chongqing Med Univ, Prenatal Diag Ctr, Women & Childrens Hosp, Chongqing 401147, Peoples R China; [Geng, Yanqing] Chongqing Med Univ, Coll Basic Med, Chongqing, Peoples R China; [Wu, Wei] Chinese Peoples Liberat Army Gen Hosp, Med Ctr 3, Sr Dept Ophthalmol, Beijing 100039, Peoples R China

通信作者：Gu, HY; Liu, XQ (通讯作者)，Chongqing Med Univ, Dept Obstet & Gynecol, Women & Childrens Hosp, 120 Longshan Rd, Chongqing 401147, Peoples R China.; Gu, HY (通讯作者)，Chongqing Municipal Hlth Commiss Key Lab Perinatal, Chongqing 400016, Peoples R China.; Liu, XQ (通讯作者)，Chongqing Med Univ, Sch Publ Hlth & Management, Dept Reprod Biol, Joint Int Res Lab Reprod & Dev, 1 Yixueyuan Rd,Box 197, Chongqing 400016, Peoples R China.; Wu, W (通讯作者)，Chinese Peoples Liberat Army Gen Hosp, Med Ctr 3, Sr Dept Ophthalmol, Beijing 100039, Peoples R China.

来源：JOURNAL OF NANOBIOTECHNOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001220824800008

JCR分区：Q1

影响因子：10.6

年份：2024

卷号：22

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Ti3C2 nanosheets; Autophagy; PI3K/AKT/mTOR; Hormone; Follicle

摘要：Background Two-dimensional ultrathin Ti3C2 (MXene) nanosheets have gained significant attention in various biomedical applications. Although previous studies have described the accumulation and associated damage of Ti3C2 nanosheets in the testes and placenta. However, it is currently unclear whether Ti3C2 nanosheets can be translocated to the ovaries and cause ovarian damage, thereby impairing ovarian functions. Results We established a mouse model with different doses (1.25, 2.5, and 5 mg/kg bw/d) of Ti3C2 nanosheets injected intravenously for three days. We demonstrated that Ti3C2 nanosheets can enter the ovaries and were internalized by granulosa cells, leading to a decrease in the number of primary, secondary and antral follicles. Furthermore, the decrease in follicles is closely associated with higher levels of FSH and LH, as well as increased level of E-2 and P-4, and decreased level of T in mouse ovary. In further studies, we found that exposure toTi(3)C(2) nanosheets increased the levels of Beclin1, ATG5, and the ratio of LC3II/Iota, leading to autophagy activation. Additionally, the level of P62 increased, resulting in autophagic flux blockade. Ti3C2 nanosheets can activate autophagy through the PI3K/AKT/mTOR signaling pathway, with oxidative stress playing an important role in this process. Therefore, we chose the ovarian granulosa cell line (KGN cells) for in vitro validation of the impact of autophagy on the hormone secretion capability. The inhibition of autophagy initiation by 3-Methyladenine (3-MA) promoted smooth autophagic flow, thereby partially reduced the secretion of estradiol and progesterone by KGN cells; Whereas blocking autophagic flux by Rapamycin (RAPA) further exacerbated the secretion of estradiol and progesterone in cells. Conclusion Ti3C2 nanosheet-induced increased secretion of hormones in the ovary is mediated through the activation of autophagy and impairment of autophagic flux, which disrupts normal follicular development. These results imply that autophagy dysfunction may be one of the underlying mechanisms of Ti3C2-induced damage to ovarian granulosa cells. Our findings further reveal the mechanism of female reproductive toxicity induced by Ti3C2 nanosheets.

基金机构：Postdoctoral Program of Chongqing Natural Science Foundation

基金资助正文：The authors would like to thank Beijing Zhongkebaice Technology Co., Ltd. and Shanghai Yanhui Biotechnology Co., Ltd. for their excellent technical support.