| Title: | Loss of p16 does not protect against premature ovarian insufficiency caused by alkylating agents |
| Author(s): | Liu F; Wan Q; Liu P; Miao D; Dai X; Chen L; |
| Address: | "The Center for Reproductive Medicine, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, China. Kebiao Medical Testing Center, Changzhou, Jiangsu, China. The Research Center for Aging, Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China. The Center for Reproductive Medicine, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, China. daixiuliang@126.com. The Center for Reproductive Medicine, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, China. czrcchenli@126.com" |
| DOI: | 10.1186/s12884-023-05476-x |
| ISSN/ISBN: | 1471-2393 (Electronic) 1471-2393 (Linking) |
| Abstract: | "BACKGROUND: Chemical agents such as alkylating agents (AAs) that are commonly used for the treatment of cancer cause great damage to the ovaries, thereby significantly increasing the risk of premature ovarian insufficiency (POI). However, the exact molecules underlying AA-induced POI remain largely obscure. Upregulation of the p16 gene may contribute to the progression of POI. As yet, no in vivo data from p16-deficient (KO) mice are available to demonstrate a critical role of p16 in POI. In the present study, we employed p16 KO mice to investigate whether loss of p16 could protect against POI caused by AAs. METHODS: WT mice and their p16 KO littermates received a single dose of BUL + CTX to establish an AA-induced POI mouse model. One month later, oestrous cycles were monitored. Three months later, some of the mice were sacrificed to collect sera for measurements of hormone levels and ovaries for measurements of follicle counts, the proliferation and apoptosis of granulosa cells, ovarian stromal fibrosis and vessels. The remaining mice were mated with fertile males for the fertility test. RESULTS: Our results showed that treatment with BUL + CTX significantly disrupted the oestrous cycles, increased the levels of FSH and LH while decreasing the levels of E2 and AMH, decreased the counts of primordial follicles and growing follicles while increasing the counts of atretic follicles, reduced the vascularized area in the ovarian stroma, and decreased fertility. All of these results were comparable between WT and p16 KO mice treated with BUL + CTX. In addition, ovarian fibrosis was not increased significantly in WT and p16 KO mice treated with BUL + CTX. Growing follicles with normal appearance had normally proliferating granulosa cells (without apparent apoptosis). CONCLUSION: We concluded that genetic ablation of the p16 gene did not attenuate ovarian damage or help preserve the fertility of mice challenged by AAs. This study demonstrated for the first time that p16 is dispensable for AA-induced POI. Our preliminary findings suggest that targeting p16 alone may not preserve the ovarian reserve and fertility of females treated with AAs" |
| Keywords: | Male Female Mice Humans Animals *Alkylating Agents/toxicity *Primary Ovarian Insufficiency/chemically induced/prevention & control/genetics Ovarian Follicle Granulosa Cells Alkylating agents Folliculogenesis Premature ovarian insufficiency p16 deficiency; |
| Notes: | "MedlineLiu, Fei Wan, Qin Liu, Pengfei Miao, Dengshun Dai, Xiuliang Chen, Li eng 81901436/National Natural Science Foundation of China/ CZQM2020094/Changzhou Health Committee Funded Young Investigator Training Project/ ZD201921/Key Program of Changzhou Municipal Health Commission/ England 2023/03/09 BMC Pregnancy Childbirth. 2023 Mar 8; 23(1):151. doi: 10.1186/s12884-023-05476-x" |
