According to statistics, the rate of unintended pregnancies is as high as 50% worldwide. Of the contraceptive methods currently available, which are mainly for women, there are very few contraceptive options for men and onlywithVasectomy。But *** is disposable, and it is easy to fail contraception. Vasectomy, on the other hand, can sometimes be reversed, but it is expensive and not always successful, so it can almost be considered a permanent form of sterilization.
Scientists have been working to develop effective male contraceptives for decades, but so far they have not been successful. At present, the male contraceptives in clinical trials are basically hormonal drugs, targeting the male hormone testosterone, these hormonal male contraceptives are very effective, but can cause weight gain, depression, increased LDL cholesterol levels, etc
Therefore, there is a need to find new, safe, and reversible methods of male contraception, but because the process of sperm development is very complex, researchers have struggled to determine which parts of the process can be safely and effectively intervened.
February 20, 2024, Salk Instituteronald evansThe team is featured in theProceedings of the National Academy of Sciences(PNAS) titled "Targeting Nuclear Receptor Corepressors for Reversible Male Contraception**.
The study found that inhibition of SMRT-retinoic acid receptor-HDAC complex activity interrupted spermatogenesis, and this process was non-hormonal and reversible. The study further demonstrates the use of existing drugsHistone deacetylase（hdac）Inhibitors, which can interfere with the function of this protein complex, thereby interrupting sperm production without affecting libido, and more importantly, the method is non-hormonal and reversible.
*Corresponding authorronald evansThe professor said the method is very sophisticated, which makes it a promising candidate for male contraceptives, and we hope to see its progress in human clinical trials soon.
Men are constantly producing new sperm every day, and in order to do this, the sperm stem cells in ** are constantly replicating themselves until a signal tells them that it's time to turn into sperm – a process known as:Spermatogenesis, this signal is an intermediate metabolite of vitamin ATretinoin(Also called.)Retinoic acid) in the form of appearance. Tretinoin binds to retinoids in cells, which in turn initiates a complex genetic process that turns sperm stem cells into mature sperm.
In this study, the research team found that for the above process to be achieved, the tretinoin receptor must interact with a receptor calledsmrtThe protein binds, and then, SMRT recruitsHistone deacetylase(HDAC), this protein complex continues to synchronously produce gene expression for spermatozoa.
Previous research teams have tried to stop sperm production by directly blocking tretinoin or its receptors. But tretinoin is important for multiple organ systems, so blocking throughout the body can lead to a variety of *** which is why many previous studies and trials ultimately failed to produce usable drugs. Therefore, in this latest study, the research team tried to produce a more targeted effect by modulating the molecule downstream of tretinoin to produce a more targeted interruption of sperm production.
The research team first looked at a group of genetically engineered mice previously developed in the lab whose SMRT protein was mutated and could no longer bind to the retinoid receptor. Without this SMRT-retinoid receptor interaction, mice were unable to produce mature spermatozoa, and they exhibited normal androgen levels and mating behavior, suggesting that their desire to mate was not affected.
To further confirm whether the effects observed in the above genetically engineered mice can be achieved with a drug intervention, the research team usedms-275**Normal mice, which is an oral HDAC inhibitor that has been approved by the FDA for human clinical trials. The results showed that MS-275 successfully suspended sperm production by blocking the activity of the SMRT-Tretinoin receptor-HDAC complex without significant *** In addition, within 60 days after discontinuation of the drug, the fertility of the mice would be fully restored, and all subsequent offspring would develop healthy.
Histone deacetylase inhibitors block spermatogenesis in mice.
According to the research team, the strategy of inhibiting the downstream molecule of tretinoin proposed in the study is the key to achieving this reversible contraception. They imagined the genes related to tretinoin and sperm production as two dancers in a waltz whose rhythm and pace needed to be in harmony with each other in order to dance. But if you let their pace be out of tune, the whole dance will fall apart. In this case, HDAC inhibitors cause a "gait dysregulation" of genes, which in turn stops the "dance" of sperm production. Removing HDAC inhibitors allows them to regain their rhythm and pace, allowing sperm production to return to normal levels.
What's more, the drug does not compromise the integrity of sperm stem cells or their genomes, sperm stem cells simply continue to regenerate in the form of stem cells when the drug is present, and when the drug is removed, sperm stem cells are able to regain their ability to differentiate into mature sperm.
*: Biological world：pnas.org/doi/abs/10.1073/pnas.2320129121