Meiotic prophase I disruption as a strategy for nonhormonal male contraception using small-molecule inhibitor JQ1
Abstract
Developing safe, reversible, and nonhormonal male contraceptives has been hindered by the lack of defined biological windows that can be transiently interrupted without compromising long-term fertility. Here, we tested whether meiotic prophase I can serve as such a window by pharmacologically inhibiting the testis-specific chromatin reader BRDT using the small-molecule bromodomain inhibitor (+)-JQ1 as proof-of-principle. Short-term JQ1 administration (3 wk) selectively disrupted the pachytene transcriptional program, depleted postmeiotic germ cells, and induced a reversible arrest in spermatogenesis. Upon drug withdrawal, prophase I cytological markers normalized within 6 wk, accompanied by restoration of testis architecture and germ-cell composition. Crossover metrics and transcriptional programs recovered more gradually, reaching full normalization by 30 wk alongside complete restoration of fertility and fecundity. These results demonstrate that meiotic prophase I can be transiently inhibited to suppress spermatogenesis reversibly without inducing lasting genomic or reproductive defects, defining a stage-specific framework for the rational design of nonhormonal male contraceptives.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (12)
Stephanie Tanis
Department of Biomedical Sciences and Cornell Reproductive Sciences Center, College of Veterinary Medicine, Cornell University
Leah E. Simon
Department of Biomedical Sciences and Cornell Reproductive Sciences Center, College of Veterinary Medicine, Cornell University
Adriana K. Alexander
Department of Biomedical Sciences and Cornell Reproductive Sciences Center, College of Veterinary Medicine, Cornell University
Tegan S. Horan
Department of Biomedical Sciences and Cornell Reproductive Sciences Center, College of Veterinary Medicine, Cornell University
Maria de las Mercedes Carro
Department of Biomedical Sciences and Cornell Reproductive Sciences Center, College of Veterinary Medicine, Cornell University
Samantha Jane Bonnett
Department of Biomedical Sciences and Cornell Reproductive Sciences Center, College of Veterinary Medicine, Cornell University
Audrey Xie
Department of Biomedical Sciences and Cornell Reproductive Sciences Center, College of Veterinary Medicine, Cornell University
Roni Ben-Shlomo
Department of Biomedical Sciences and Cornell Reproductive Sciences Center, College of Veterinary Medicine, Cornell University
Connor E. Owens
Department of Biomedical Sciences and Cornell Reproductive Sciences Center, College of Veterinary Medicine, Cornell University
Charles G. Danko
Department of Biomedical Sciences and Cornell Reproductive Sciences Center, College of Veterinary Medicine, Cornell University
Jelena Lujic
Department of Biomedical Sciences and Cornell Reproductive Sciences Center, College of Veterinary Medicine, Cornell University
Paula E. Cohen
Department of Biomedical Sciences and Cornell Reproductive Sciences Center, College of Veterinary Medicine, Cornell University