Contraception: Stopping sperm in their tracks

An automated high-throughput platform can screen for molecules that change the motility of sperm cells and their ability to fertilize.
  1. Luke L McGoldrick
  2. Jean-Ju Chung  Is a corresponding author
  1. Department of Cellular and Molecular Physiology, Yale School of Medicine, United States
  2. Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, United States

From 2010 to 2014, about 44% of pregnancies worldwide were unplanned, and over half of these ended in abortion in both developed and developing countries (Bearak et al., 2018). Moreover, these terminations frequently result in the death of women in some regions of the world (Ganatra et al., 2017; WHO, 2011). These statistics confirm the need to make effective family planning more widely available to those who want to adopt it, as this brings positive outcomes to women, families, countries and the environment (Starbird et al., 2016).

Precursors to the modern condom were used in ancient Egypt, and hormone-based female oral contraceptives have been used since the middle of the twentieth century (Khan et al., 2013; Dhont, 2010). Today, most contraceptives are for use by women. Traditional male options include condoms, which are only partially effective, and vasectomies, which men may be hesitant to get because they cannot always be reversed (Manetti and Honig, 2010; Gava and Meriggiola, 2019). There is therefore a need for new male contraceptives, with sperm being an obvious target.

Sperm cells are equipped with a tail-like structure that allows them to be motile and to travel through the female reproductive tract to reach the egg. There, they undergo the acrosome reaction: this involves the sperm cell releasing digestive enzymes that allow it to come into close contact and fuse with an egg. Successful fertilization requires both motility and a successful acrosome reaction, so targeting and disrupting these processes is a good strategy to develop effective male contraceptives.

Now, in eLife, Franz Gruber, Zoe Johnston, Christopher Barratt and Paul Andrews at the University of Dundee report having developed a new screening platform to evaluate the effects of small molecules on the motility of sperm cells and their ability to go through the acrosome reaction (Gruber et al., 2020). The team used a collection of about 12,000 clinical or preclinical small molecules for which human safety data are already available.

To evaluate the effect these molecules have on sperm motility, a robotics system was used to incubate each small molecule with separate batches of sperm for 10 minutes (Figure 1); the cells were then imaged using a camera with a high frame rate to capture motion. In total, 63 candidates were identified as reducing motility by 15% or more, with 29 being confirmed when retested. Some of the hits were promising, such as Disulfiram and KF-4939. Disulfiram has been used to treat alcohol dependency and is known to dampen sperm motility (Lal et al., 2016). KF-4939 is thought to inhibit platelet aggregation factors, which have already been used in male infertility treatments to improve sperm motility (Roudebush et al., 2004). The experiment also highlighted a large number of small molecules that increase, rather than decrease, sperm motility: these molecules need to be investigated further as they could be used to treat infertility.

Automated targeting of sperm motility and acrosome reaction with small molecules.

Sperm are robotically allocated into wells (~10,000 cells/well) in a 384-well plate (top left); each well contains a different small molecule at a concentration of ~6 μM. The insets show KF-4939, an anti-platelet agent, binding to sperm cells. After incubation with the small molecules, sperm motility is imaged and assessed (middle left). Subsequently, the same sperm are mixed with two tags, peanut agglutinin (PNA; green) and propidium iodide (Pi; red), that emit fluorescence when attached to cells. Sperm were analyzed with a technique called flow cytometry (top right): PNA binding to a sperm cell indicates that the cell has undergone the acrosome reaction, while Pi only binds to dead cells. Most sperm cells do not bind to PNA or Pi, some bind to one but not the other, and some bind to both (bottom right).

To improve the efficiency of the screen, the same cells that had been assessed for motility were also examined for the acrosome reaction. Two fluorescent tags, called peanut agglutinin and propidium iodide, helped to detect sperm cells that had gone through the reaction after being exposed to the small molecules. Peanut agglutinin only binds to the heads of sperm cells that have undergone the acrosome reaction, and propidium iodide exclusively attaches to dead cells. An automated technique called flow cytometry was used to record whether the tags were bound to a given cell, therefore measuring the percentage of live cells that had undergone the acrosome reaction after being exposed to the small molecules. However, all nine hits proved to be false positives as the small molecules themselves were fluorescent, highlighting a need to carry on such screenings while being wary of artefacts.

The high-throughput screening platform developed by Gruber et al. has the potential to make important contributions to the search for contraceptives and male infertility drugs. This work only examined one collection of molecules, and two sperm parameters, motility and acrosome reaction. Going forward, it would be interesting to apply this platform to target other aspects of sperm biology that are critical for fertilization, such as hyperactivated motility (when sperm cells vigorously and asymmetrically wag their tail-like structures to enter the egg), or the binding of sperm cells to specific egg proteins.

References

    1. Dhont M
    (2010) History of oral contraception
    The European Journal of Contraception & Reproductive Health Care 15:S12–S18.
    https://doi.org/10.3109/13625187.2010.513071
    1. Gava G
    2. Meriggiola MC
    (2019) Update on male hormonal contraception
    Therapeutic Advances in Endocrinology and Metabolism 10:204201881983484.
    https://doi.org/10.1177/2042018819834846

Article and author information

Author details

  1. Luke L McGoldrick

    Luke L McGoldrick is in the Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8310-7502
  2. Jean-Ju Chung

    Jean-Ju Chung is in the Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, United States

    For correspondence
    jean-ju.chung@yale.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8018-1355

Publication history

  1. Version of Record published: February 27, 2020 (version 1)

Copyright

© 2020, McGoldrick and Chung

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,810
    Page views
  • 129
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Luke L McGoldrick
  2. Jean-Ju Chung
(2020)
Contraception: Stopping sperm in their tracks
eLife 9:e55396.
https://doi.org/10.7554/eLife.55396

Further reading

    1. Computational and Systems Biology
    2. Developmental Biology
    Mohamad Ibrahim Cheikh, Joel Tchoufag ... Konstantin Doubrovinski
    Research Article

    In order to understand morphogenesis, it is necessary to know the material properties or forces shaping the living tissue. In spite of this need, very few in vivo measurements are currently available. Here, using the early Drosophila embryo as a model, we describe a novel cantilever-based technique which allows for the simultaneous quantification of applied force and tissue displacement in a living embryo. By analyzing data from a series of experiments in which embryonic epithelium is subjected to developmentally relevant perturbations, we conclude that the response to applied force is adiabatic and is dominated by elastic forces and geometric constraints, or system size effects. Crucially, computational modeling of the experimental data indicated that the apical surface of the epithelium must be softer than the basal surface, a result which we confirmed experimentally. Further, we used the combination of experimental data and comprehensive computational model to estimate the elastic modulus of the apical surface and set a lower bound on the elastic modulus of the basal surface. More generally, our investigations revealed important general features that we believe should be more widely addressed when quantitatively modeling tissue mechanics in any system. Specifically, different compartments of the same cell can have very different mechanical properties; when they do, they can contribute differently to different mechanical stimuli and cannot be merely averaged together. Additionally, tissue geometry can play a substantial role in mechanical response, and cannot be neglected.

    1. Developmental Biology
    2. Evolutionary Biology
    Kwi Shan Seah, Vinodkumar Saranathan
    Research Article

    The study of color patterns in the animal integument is a fundamental question in biology, with many lepidopteran species being exemplary models in this endeavor due to their relative simplicity and elegance. While significant advances have been made in unraveling the cellular and molecular basis of lepidopteran pigmentary coloration, the morphogenesis of wing scale nanostructures involved in structural color production is not well understood. Contemporary research on this topic largely focuses on a few nymphalid model taxa (e.g., Bicyclus, Heliconius), despite an overwhelming diversity in the hierarchical nanostructural organization of lepidopteran wing scales. Here, we present a time-resolved, comparative developmental study of hierarchical scale nanostructures in Parides eurimedes and five other papilionid species. Our results uphold the putative conserved role of F-actin bundles in acting as spacers between developing ridges, as previously documented in several nymphalid species. Interestingly, while ridges are developing in P. eurimedes, plasma membrane manifests irregular mesh-like crossribs characteristic of Papilionidae, which delineate the accretion of cuticle into rows of planar disks in between ridges. Once the ridges have grown, disintegrating F-actin bundles appear to reorganize into a network that supports the invagination of plasma membrane underlying the disks, subsequently forming an extruded honeycomb lattice. Our results uncover a previously undocumented role for F-actin in the morphogenesis of complex wing scale nanostructures, likely specific to Papilionidae.