Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Targeting a protein important for chromatin organization could be a new strategy for male birth control. Proper regulation of chromatin dynamics is critical for proper sperm development, and mice with alterations in a protein that is central to chromatin organization are infertile. Now, scientists show that treating mice with a drug known to inhibit that protein impedes sperm development and renders the animals infertile—but halting treatment allows sperm production to restart and mice to sire normal litters.
The results, published in Cell, suggest that targeting this protein could produce a safe, reversible method for non-hormonal male contraception—a long-sought goal that has so far failed to materialize as an option alongside condoms and vasectomies.
Hormonal male contraception methods are already well-established. Male hormonal contraception works at least as well as a typical female oral contraceptive pill. But such contraceptives still have some significant hurdles to overcome before making it to market.
First, the strategy, which involves administering a hormone (usually a progestin) to halt production of testosterone and thus inhibit sperm development, does not suppress sperm production enough in every man. It also requires dosing with enough exogenous testosterone to maintain libido and muscle mass, but there’s currently no cheap and easily applied testosterone on the market. Furthermore, hormone-based male contraception can cause side effects. Unlike side effects for the female hormonal contraception, these can’t be balanced against the risks of pregnancy, which are often higher, noted John Amory at the University of Washington. Because men don’t run the same medical risks of pregnancy, there’s a higher bar for ensuring that contraception administered to healthy men doesn’t carry risks. Finally, despite worldwide surveys suggesting public receptiveness to a male contraceptive pill, pharmaceutical companies no longer fund development of such drugs.
Some of these issues have spurred researchers to look for a non-hormonal way to temporarily induce infertility in men, which should cause with fewer side effects and be more appealing to pharma. Amory’s work, for example, has shown that a compound that targets the retinoic acid pathway of sperm development reversibly inhibits sperm production. The drug’s potential is hamstrung by the fact that men taking the drug can’t consume alcohol without nausea—a side effect he’s currently working to circumvent.
The current study builds on previous work by Debra Wolgemuth at Columbia University showing that BRDT—a testes-specific member of a family of bromodomain-containing proteins, which are important for regulating chromatin organization in various tissues—was critical for normal sperm development in mice. Truncating BRDT has an amazing effect on haploid sperm development. Removing the first bromodomain results in production of a shortened protein and, consequently, the aberrant organization and packaging of DNA in the sperm cells produced. Spermatids fail to elongate normally in mutant mice, resulting in decreased sperm production, misshapen sperm, and infertility.
In order to test the possibility that a BRDT-inhibiting drug, JQ1, might have potential as a male contraceptive, Martin Matzuk of Baylor College of Medicine and his collaborators injected male mice daily with the drug, and examined their testis volume. This volume, which reflects the amount of sperm in the testes, dropped by 60 percent over the 6 weeks of treatment. The sperm count of these mice was nearly 90 percent lower than in control mice, and sperm motility also plunged in JQ1-treated mice, collectively resulting in infertility. Though JQ1 is known to inhibit related proteins expressed elsewhere in the body, the mice seemed to have no other effects from JQ1 treatment, and normal hormone levels in treated mice suggested that infertility wasn’t the result of a hormone imbalance.
A closer look at sperm generation in JQ1-treated mice suggested that sperm development was primarily blocked after the sperm cells had undergone meiosis, but before they began the process of elongating—a similar stage to that seen in BRDT-mutant mice. Importantly, the mice regained the ability to sire pups after several weeks off the drug.
The reversibility of the treatment is likely attributable to the fact that the researchers are targeting sperm cells midway through development, rather than accessory cells that support sperm development from stem cells, noted Michael Griswold, who studies sperm cell development at Washington State University, but did not participate in the study. It’s “a great place to inhibit, because you don’t get sperm cells, but you don’t affect stem cells, which makes [the treatment] reversible,” he explained.
Whether JQ1 acts by primarily targeting BRDT and derailing chromatin organization or whether it inhibits other family members expressed during sperm development remains unclear. Matzuk and his colleagues examined gene expression in JQ1-treated and control mice, and saw decreased expression of many genes important for meiosis, suggesting that JQ1 may be working by affecting transcription of a suite of important genes for spermatogensis. Also, because JQ1 also inhibits BRDT-related proteins, researchers need to be watchful for long-term side effects not detected in the current study, Matzuk noted. Going forward, it will be important to design drugs that selectively target BDRT.
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Great post thank you, i’ll post it on my Groups for hits and sharing
Thanks for sharing
[…] Hope for Male Contraception: A small molecule that inhibits a protein important for chromatin organi… […]
[…] Hope for Male Contraception: A small molecule that inhibits a protein important for chromatin organi… […]
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.