Abstract
SummaryA pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood:testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception.PaperClip
Highlights
$4% of the mammalian genome encodes genes expressed in male germ cells during spermatogenesis (Schultz et al, 2003), contraceptive drugs for men have remained elusive
BRDT is a tissue-restricted, chromatin-associated protein expressed in pachytene spermatocytes, diplotene spermatocytes, and round spermatids (Shang et al, 2007)
Testosterone levels or mating behaviors and without prompting obvious teratogenic effects in offspring. These results indicate that targeting a developmental epigenetic reader protein with an orally bioavailable small molecule can modulate male fertility for a contraceptive effect
Summary
$4% of the mammalian genome encodes genes expressed in male germ cells during spermatogenesis (Schultz et al, 2003), contraceptive drugs for men have remained elusive. The only drugs in clinical trials are testosterone analogs that alter endogenous androgen production, there is a short list of other possible targets (e.g., GAPDHS) and drugs (e.g., gamendazole) (Aitken et al, 2008) This lack of contraceptive alternatives for men is partially responsible for the high rate of unplanned pregnancies, especially in teenagers, and contributes to the maternal mortality, ethical, social, and financial costs associated with abortions and deliveries to single mothers. To approach this dearth of contraceptive alternatives for men, we have undertaken to develop small molecules that could target spermatogenic-specific proteins that have been shown to be essential for both spermatogenesis and fertility in mammals. Genetic studies of BRDT have demonstrated that selective deletion of the BRDT(1)-encoding region is sufficient to confer sterility in
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