Introduction

Sperm, when fused to a female female oocyte, provide the male contribution of genomic information, enabling a fully functional progeny to develop. Sperm also contribute a centrosome, sperm borne oocyte activating factors (SOAFs) and possibly mRNA to the oocyte in order to initiate oocyte activation, the utilisation of maternal resources and the generation of a dividing embryo. The main function of sperm is to transport genomic information from a male to the female, travelling a distance of 15cm, which is equivalent to a human swimming 40 miles. On its journey sperm must travel through the torturous environment of the acidic vaginal passage, cervical mucus, uterus and fallopian tube. In order to reach its destination and fertilise an oocyte, sperm have become higly specialised mobile cells.

Figure 1. Diagram of a Spermatozoon



Figure 2. Axenome

Figure 2 shows a cross section of an axenome filament that runs throughout the sperms tail. The axen

Table 1: Features of Sperm Cells



Spermatogenesis

Spermatogenesis produces haploid male gametes that are able to fertilise a mature oocyte. Due to the limited life span of sperm cells, production is a continous process and maintains a daily output of >200 million differentiated sperm. Sperm production has many steps and from start to finish takes approximately 64 days in humans. Sperm production can be split into 3 stages: spermatogenesis, spermatidogenesis and spermiogenesis.

Figure 3. Spermatogenesis



Spermatogenesis takes place in the seminiferous tubules of the testes, which are relatively quiescent and not fully differentiated prior to puberty. Testes develop from primordial germ cells in the epiblast, which migrate to the hind-gut and colonise the genital ridge. Upon activation by the SRY gene, primordial germ cells cause the development of male characteristic gonads. Fully differentiated testes contain 12-20 seminiferous tubules with both ends flowing into the rete testis.

The unique architecture of the seminiferous tubules provides a self-contained environment supplying all necessary nutrients needed by developing sperm and isolating the lumen from the body's immune system. Spermatogenesis requires an immune privaleged site due to the highly antigenic coats of developing sperm. Antibodies in the blood can hinder sperm function durring maturation, transit through the testis and fertilisation.

 

Spermatogenesis - production of haploid gemetes

Spermatogenesis begins with spermatogonia, the primordial germ cells of sperm production. Spermatogonia are mitotically inactive until the peri pubertal period where an increase in gonadotrophin hormones from leydig cells of the testes induces massive mitotic proliferation. Spermatogonia then enter meiosis by differentiating into primary spermatocytes. Primary spermatocytes can either self-renew or divide into two secondary spermatocytes completing meiosis one (figure 3).

 

Spermatidogenesis - production of spermatids

Secondary spermatocytes then divide into four spermatids in order to complete meiosis two (figure 3). Spermatids then have many steps of sperm accessory structure biogenesis to form fully differentiated sperm. This process is called spermiogenesis. Throughout the processes of spermatogenesis, spermatidogenesis and spermiogenesis all spermatogenic cells remain associated with sertoli cells in the seminiferous tubules via cytoplasmic bridges (figure 4). Sertoli cells provide nutrients and signals such as testosterone and FSH required to stimulate and develop each stage of sperm production.

 

Spermiogenesis involves:

  • Elongation to produce tail and all its components e.g. axenome and mitochondrial sheath.
  • Spermatids Golgi apparatus is modified in order to form the perinuclear theca.
  • Morphogenesis of the sperm head to a spatulate shape.
  • Nuclear hypercondensation in which histones are replaced with protamines, therby condensing the genetic material and making the genome transcriptionally inactive.
  • Removal and degradation of unneeded organelles and proteins in order to achieve motility. Ubiquitin marks proteins for degradation and recycling via the proteasome.
  • Maturation of the sperm induced by the input of testosterone from sertoli cells. Maturation involves the removal of remaining unneeded cytoplasm and organelles, which are then phagocytosed by neighbouring sertoli cells.

 

As spermatids develop, they migrate away from the basement membrane of the seminiferous tubules moving towards the lumen. When fully differentiated and mature, sperm cells are released from sertoli cell cytoplasmic bridges and bud off into the lumen of the seminiferous tubules (figure 4). Mature sperm cells are unable to swim so are transported into the epididymus for storage by peristaltic contractions of the seminiferous tubules. The large mass and number of sperm entering the lumen coupled with active fluid secretion by sertoli cells also produces a pressure that pushes the sperm along the seminiferous tubules. In the epididymus, maturation of the sperm continues and the sperm gain the ability to swim prior to ejaculation.

Figure 4. Seminiferous Tubules of the Testes



Regulation of Sperm Production

Multiple intrinsic factors are produced in the seminiferous epithelium to regulate and maintain spermiogenesis. These include stem cell renewal factors c-Kit tyrosine kinase receptors and its ligands, and transcription factors such as Oct3/4 and CREB/CREM.

As sperm production is a continuous process involving mass proliferation, quality control is required to prevent the production of imperfect or damaged sperm. Quality control involves:

  • DNA repair molecules: E3 ubiquitin ligase, gonadotrophin regulated testicular RNA helicase GRTH/Ddx25, and DNA repair protein Dmc1.
  • Apoptosis regulators: Bax, Bcl-2, Fas/FasL and various caspases that are involved in quality control via apoptosis.

Sensitivity of Sperm Production

50% of infertility cases are due to problems in the male partner. Damage to DNA in the male germ line has shown to have serious consequences for the health and development of offspring. Reccurent miscarriages can be caused by damage to genes involved in placental development, many of which are paternally inherited. Sperm DNA damage rates are higher in smokers, older men and individuals who have undergone cancer therapies.

Testicular function is temperature sensitive, which has led to the development of descended testicles in order to keep testicles between 2 and 8 degrees celsius below core body temperature. Heat shock experiments on mice testicles caused damage to chromatin structure, impaired DNA repair mechanisms, reduced fertility, reduced placental weight in successful pregnancies and caused abnormal embryo growth develepment. There is a correlation with male testicular heat stress and infertility that can be experienced in occupations such as bakers, welders, and professional drivers or people with bad posture and tight fitting clothing. High testicular temperatures clearly affect the quality of sperm and consequently fertility. The use of sperm with damaged DNA for intracytoplasmic sperm injection could therefore have long-term health effects for the resultant children.

References

  • Pires, Pieri, Hage, Santos, Medeiros, Garcia, Yonamine, Hallak, Saldiva, Zorzetto, Bueno (2012) Repeated inhalation of crack-cocaine affects spermatogenesis in young and adult mice, Inhal Toxicol, 24 (7) 439-46
  • McCabe, Allan, Foo, Nicholls, McTavish, Stanton (2012) Androgen initiates sertoli cell tight junction formation in the hypogonadal (hgd) mouse, Biol Reprod 
  • Rato, Alves, Socorro, Duarte, Cavaco, Oliveira (2012) Metabolic regulation is important for spermatogenesis, Nat Rev Urol
  • Collins (2003) The androgen receptor in spermatogenesis, Cytogenet Genome Res, 103 (3-4), 299-301
  • Brinster (2007) Male germline stem cells: from mice to men, Science, 316 (5823), 404-5
  • Shukla, Mahdi, Rajender (2012) Apoptosis, spermatogenesis & Male Infertility, Front Biosci, 1 (4) 746-54
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