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Small-molecule inhibition of BRDT for male contraception.

Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE - Cell (2012)

Bottom Line: 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.Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. mmatzuk@bcm.edu

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Reversal of Testicular Phenotypes following Withdrawal of JQ1, Related to Figure 7(A–C) Analysis of (A) testicular mass, (B) sperm counts, and (C) sperm motility of adult male mice treated for 3 weeks with JQ1 (50 mg/kg QD), followed by euthanasia at the end of treatment (JQ1), 2 months following cessation of treatment, and 4 months following cessation of treatment. Normalization of all parameters is evident following drug withdrawal. Data represent mean ± SEM.(D and E) Testis histology (10X) of tubules from control and JQ1-treated male mice 4 months following cessation of JQ1 as treated in (A-C).(F) Graphical representation of tubule area calculated from histological preparations of testis tubules from male mice following four month recovery from the low-dose (Figure 6A) regimen. Data represent mean ± SEM.(G) Graphical representation of tubule area calculated from histological preparations of testis tubules from male mice during and following 10 day, 30 day, and 60 day recovery from a 3 week period of JQ1 BID treatment. Data represent mean ± SEM (∗, significant at p < 0.05).(H) A single pup born from a JQ1-treated male after halting JQ1 treatment. Normal developmental and behavioral phenotypes are observed in offspring of mice with restored fertility following a period of contraception conferred by JQ1 treatment.
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figs4: Reversal of Testicular Phenotypes following Withdrawal of JQ1, Related to Figure 7(A–C) Analysis of (A) testicular mass, (B) sperm counts, and (C) sperm motility of adult male mice treated for 3 weeks with JQ1 (50 mg/kg QD), followed by euthanasia at the end of treatment (JQ1), 2 months following cessation of treatment, and 4 months following cessation of treatment. Normalization of all parameters is evident following drug withdrawal. Data represent mean ± SEM.(D and E) Testis histology (10X) of tubules from control and JQ1-treated male mice 4 months following cessation of JQ1 as treated in (A-C).(F) Graphical representation of tubule area calculated from histological preparations of testis tubules from male mice following four month recovery from the low-dose (Figure 6A) regimen. Data represent mean ± SEM.(G) Graphical representation of tubule area calculated from histological preparations of testis tubules from male mice during and following 10 day, 30 day, and 60 day recovery from a 3 week period of JQ1 BID treatment. Data represent mean ± SEM (∗, significant at p < 0.05).(H) A single pup born from a JQ1-treated male after halting JQ1 treatment. Normal developmental and behavioral phenotypes are observed in offspring of mice with restored fertility following a period of contraception conferred by JQ1 treatment.

Mentions: To assess the reversibility of the JQ1-induced contraceptive effect, we examined whether fertility returned after JQ1 treatment was halted. Among the three infertile mice treated with the low-dose regimen, infertility remained complete at 1 month of recovery (mating month 3), indicating a durable effect of JQ1 on spermatogenesis. However, in mating month 4, all three males sired offspring with a statistically similar number of pups per female as observed for the controls (Figure 7A). The average days to effective copulation was estimated to be 31.7 ± 6.0 days (range: 26–38 days) based on the birth of the first litters after treatment was stopped and the 19 day gestation period of mice. After a total mating period of 7 months (i.e., 4 months after halting the low-dose regimen), testis volume, seminiferous tubule area, testis histology, sperm motility, and sperm counts were statistically similar to the control group (Figures 7C–7E and S4), consistent with fully recovered fertility. Thus, mice treated with JQ1 at 50 mg/kg/day and then 75 mg/kg/day recover fertility within 6 weeks of withholding the drug and show no long-term effects of JQ1 treatment. For the mice that required escalation to the high-dose regimen (50 mg/kg BID), JQ1 was halted after the first month of this treatment (i.e., treatment month 3). In months 4 and 5, these males failed to sire offspring (Figure 7B). However, all JQ1-treated males sired offspring in month 6 and sired similar litter sizes as controls in months 6–8. The average days to effective copulation for this cohort was estimated to be 65.7 ± 7.7 days (range: 58–81 days). Thus, longer JQ1 treatment and/or the increased dosage of JQ1 resulted in an extended (∼1 month) period of infertility.


Small-molecule inhibition of BRDT for male contraception.

Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE - Cell (2012)

Reversal of Testicular Phenotypes following Withdrawal of JQ1, Related to Figure 7(A–C) Analysis of (A) testicular mass, (B) sperm counts, and (C) sperm motility of adult male mice treated for 3 weeks with JQ1 (50 mg/kg QD), followed by euthanasia at the end of treatment (JQ1), 2 months following cessation of treatment, and 4 months following cessation of treatment. Normalization of all parameters is evident following drug withdrawal. Data represent mean ± SEM.(D and E) Testis histology (10X) of tubules from control and JQ1-treated male mice 4 months following cessation of JQ1 as treated in (A-C).(F) Graphical representation of tubule area calculated from histological preparations of testis tubules from male mice following four month recovery from the low-dose (Figure 6A) regimen. Data represent mean ± SEM.(G) Graphical representation of tubule area calculated from histological preparations of testis tubules from male mice during and following 10 day, 30 day, and 60 day recovery from a 3 week period of JQ1 BID treatment. Data represent mean ± SEM (∗, significant at p < 0.05).(H) A single pup born from a JQ1-treated male after halting JQ1 treatment. Normal developmental and behavioral phenotypes are observed in offspring of mice with restored fertility following a period of contraception conferred by JQ1 treatment.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
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figs4: Reversal of Testicular Phenotypes following Withdrawal of JQ1, Related to Figure 7(A–C) Analysis of (A) testicular mass, (B) sperm counts, and (C) sperm motility of adult male mice treated for 3 weeks with JQ1 (50 mg/kg QD), followed by euthanasia at the end of treatment (JQ1), 2 months following cessation of treatment, and 4 months following cessation of treatment. Normalization of all parameters is evident following drug withdrawal. Data represent mean ± SEM.(D and E) Testis histology (10X) of tubules from control and JQ1-treated male mice 4 months following cessation of JQ1 as treated in (A-C).(F) Graphical representation of tubule area calculated from histological preparations of testis tubules from male mice following four month recovery from the low-dose (Figure 6A) regimen. Data represent mean ± SEM.(G) Graphical representation of tubule area calculated from histological preparations of testis tubules from male mice during and following 10 day, 30 day, and 60 day recovery from a 3 week period of JQ1 BID treatment. Data represent mean ± SEM (∗, significant at p < 0.05).(H) A single pup born from a JQ1-treated male after halting JQ1 treatment. Normal developmental and behavioral phenotypes are observed in offspring of mice with restored fertility following a period of contraception conferred by JQ1 treatment.
Mentions: To assess the reversibility of the JQ1-induced contraceptive effect, we examined whether fertility returned after JQ1 treatment was halted. Among the three infertile mice treated with the low-dose regimen, infertility remained complete at 1 month of recovery (mating month 3), indicating a durable effect of JQ1 on spermatogenesis. However, in mating month 4, all three males sired offspring with a statistically similar number of pups per female as observed for the controls (Figure 7A). The average days to effective copulation was estimated to be 31.7 ± 6.0 days (range: 26–38 days) based on the birth of the first litters after treatment was stopped and the 19 day gestation period of mice. After a total mating period of 7 months (i.e., 4 months after halting the low-dose regimen), testis volume, seminiferous tubule area, testis histology, sperm motility, and sperm counts were statistically similar to the control group (Figures 7C–7E and S4), consistent with fully recovered fertility. Thus, mice treated with JQ1 at 50 mg/kg/day and then 75 mg/kg/day recover fertility within 6 weeks of withholding the drug and show no long-term effects of JQ1 treatment. For the mice that required escalation to the high-dose regimen (50 mg/kg BID), JQ1 was halted after the first month of this treatment (i.e., treatment month 3). In months 4 and 5, these males failed to sire offspring (Figure 7B). However, all JQ1-treated males sired offspring in month 6 and sired similar litter sizes as controls in months 6–8. The average days to effective copulation for this cohort was estimated to be 65.7 ± 7.7 days (range: 58–81 days). Thus, longer JQ1 treatment and/or the increased dosage of JQ1 resulted in an extended (∼1 month) period of infertility.

Bottom Line: 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.Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. mmatzuk@bcm.edu

Show MeSH
Related in: MedlinePlus