Revisiting the male gamete’s contribution to the conceptus: parental guidance advised

“Those who cannot change their minds cannot change anything.”

― George Bernard Shaw

Parental wisdom often takes a back seat when segueing from the childhood to teen years. As adolescence approaches, parental legacies morph from unconditional nurturing to wondering how this will all turn out when (or if) our offspring leave the nest. That this all started when our respective parental genetic contributions merged during fertilization is a given. What has become less clear over the past decade is just how much of an influence our somas may have had on gamete quality long before that fateful union of egg and sperm.

As it turns out, epigenetic modifications at key developmental transitions during gametogenesis and early stages of embryogenesis are being recognized to have major consequences at multiple stages of the life cycle. Changing our thinking, especially when it comes to the world of development beyond genetics, has not been an easy task. Classical Mendelian genetics continues to dominate thinking in the genomic world of ARTs, sometimes at the expense of opening our eyes to other matters of import having to do with enabling implantation in the hopes of achieving a term pregnancy.

What is happening well before gametes avail themselves on the road to a transferrable blastocyst? The Nature-Nurture paradigm is playing out on a microcosmic scale during gametogenesis owing to a complex series of events integrating germ cell-somatic communication in the gonads while keeping in tune with the systemic conditions holding court over the success of many events along the way.

Reporting on metabolism is but one sentinel of what the sperm will deliver to the newly formed zygote modifiers of gene expression of an extraoogenic and extraembryogenic origin [1]. Sperm cargoes of various kinds are drawn into action at the time of fertilization including organizing principles like the centrosome and even before, the spark plug that ignites egg activation-PLC-zeta. Even the ability of the male gamete to get the party going seems to require input from the reproductive tract, expanding our understanding of sperm quality from a non-genetic point of view. For example, it is time to rethink the “genome-only” contribution that prevailed in yesteryears [2] considering the various ways and means the male gamete contributes to much more than fertilization alone can explain (see in this issue Exposure to epididymal extracellular vesicles enhances immature sperm function and sustains vitality of cryopreserved spermatozoa in the domestic cat model, https://doi.org/10.1007/s10815-021-02214). Sure, having a vehicle to drive sperm movement and hence deliver the genomic cargo has always taken attention away from the underlying subtleties needed to make this as true partnership of egg and sperm, at least in those viviparous species requiring a journey to and through both reproductive tracts.

These parameters are no longer viewed as subtleties given classical studies and the emergence of complex trajectories requiring multiple adaptations and refinements over the course of evolution at least when managed in vivo [3]. Take, for example, the excitement generated from within and without the news outlets and prominent journals who collectively jumped all over the “breakthrough” studies on sperm waveform analysis last year [4]. While it seemed as though getting a handle on the biomechanics of sperm motility, including setting a compass with vectorial instincts, would tell us something useful and controllable-think sperm selection-enthusiasm once again has been dampened with the retraction of this work [5]. And, to those of us raised in the halcyon days of cell biology, this came as not much of a surprise given well known studies of Gibbons [6] and Brokaw [7] who pioneered the biochemical and biophysical dimensions of sperm motility-albeit in sea urchins-so many years ago. Some things never change!

But all is not lost as the two-sided sword of reproductive biology and medicine hold respectable and dutiful court in both understanding the causes of male infertility and setting the compass towards a day when the burden of contraception would be shifted from women to men. To wit, encouraging news has just been published on the crystal structure of Catsper, the cation channel complex in mammalian sperm, providing insights into molecular mechanisms that dictate fertility in males [8]. Strengthening the nexus between our efforts to manage infertility and provide a balanced landscape for contraception will continue to advance both domains, with or without parental guidance!