AMH protects the ovary from doxorubicin by regulating cell fate and the response to DNA damage
Abstract
Anti-Müllerian hormone (AMH) protects the ovarian reserve from chemotherapy, and this effect is most pronounced with Doxorubicin (DOX). However, DOX toxicity and AMH rescue mechanisms in the ovary have remained unclear. Herein, we characterize the consequences of these treatments in ovarian cell types using scRNAseq. DOX-induced DNA damage activates Tp53 class mediators across ovarian cell types. In the mesenchyme, cotreatment with AMH halts theca progenitor differentiation and reduces apoptotic gene expression. In preantral granulosa cells, DOX upregulates the cell cycle inhibitor Cdkn1a and dysregulates Wnt signaling, which are ameliorated by AMH cotreatment. Finally, AMH induces Id3 , a gene involved in DNA repair, which is necessary to prevent the accumulation of DNA lesions marked by γ-H2AX. Altogether these mechanisms of AMH protection contribute to sustained fertility in mice, offering promising broad avenues for fertility preservation in cancer patients undergoing chemotherapy.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Ngoc Minh Phuong Nguyen
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
Eun Mi Chang
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
Maëva Chauvin
Natalie Sicher
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
Aki Kashiwagi
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
Nicholas Nagykery
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
Christina Chow
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
Phoebe May
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
Alana Mermin-Bunnell
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
Josephine Cleverdon
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
Thy Duong
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
Motohiro Kano
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
Philippe Godin
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
Marie-Charlotte Meinsohn
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
Dadi Gao
Department of Neurology, Massachusetts General Hospital and Harvard Medical School
Patricia K. Donahoe
Pediatric Surgical Research Laboratories, Massachusetts General Hospital
David Pépin