Targeting nuclear receptor corepressors for reversible male contraception

Area of Science:

• Reproductive biology
• Molecular endocrinology
• Pharmacology

Background:

• Limited male contraceptive options exist, with condoms being unreliable and vasectomies invasive and difficult to reverse.
• Nearly half of all pregnancies are unintended, highlighting the need for effective male family planning methods.

Purpose of the Study:

• To develop a novel, non-hormonal oral male contraceptive.
• To investigate the role of the silencing mediator of retinoid and thyroid hormone receptors (SMRT) complex in spermatogenesis.
• To validate pharmacologic targeting of the SMRT repressor complex for male contraception.

Main Methods:

• Genetic engineering of mice (SMRT^mRID) to disrupt SMRT-RAR binding and studying spermatogenesis.
• Oral administration of a histone deacetylase inhibitor to block SMRT complex action in mice.
• Assessing effects on spermatogenesis, fertility, and libido.

Main Results:

• Disruption of SMRT-RAR binding in SMRT^mRID mice led to disrupted gene expression patterns crucial for spermatogenesis.
• Chronic, low-dose oral administration of a histone deacetylase inhibitor reversibly blocked spermatogenesis and fertility in mice.
• The contraceptive effect was achieved without impacting libido.

Conclusions:

• The interaction between RAR and SMRT is essential for male fertility.
• Pharmacologic targeting of the SMRT repressor complex is a viable strategy for developing a non-hormonal male contraceptive.
• This approach offers a potentially reversible and effective male family planning method.