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.