Spermatogenesis

Spermatogenesis

Seminiferous tubule with maturing sperm. H&E stain.

A mature human Spermatozoon

Anatomical terminology

Spermatogenesis is the process in which spermatozoa are produced from male primordial germ cells by way of mitosis and meiosis. The initial cells in this pathway are called spermatogonia, which yield primary spermatocytes by mitosis. The primary spermatocyte divides meiotically (Meiosis I) into two secondary spermatocytes; each secondary spermatocyte divides into two spermatids by Meiosis II. These develop into mature spermatozoa, also known as sperm cells. Thus, the primary spermatocyte gives rise to two cells, the secondary spermatocytes, and the two secondary spermatocytes by their subdivision produce four spermatozoa.[1]

Spermatozoa are the mature male gametes in many sexually reproducing organisms. Thus, spermatogenesis is the male version of gametogenesis, of which the female equivalent is oogenesis. In mammals it occurs in the seminiferous tubules of the male testes in a stepwise fashion. Spermatogenesis is highly dependent upon optimal conditions for the process to occur correctly, and is essential for sexual reproduction. DNA methylation and histone modification have been implicated in the regulation of this process.[2] It starts at puberty and usually continues uninterrupted until death, although a slight decrease can be discerned in the quantity of produced sperm with increase in age (see Male infertility).

Purpose

Spermatogenesis produces mature male gametes, commonly called sperm but specifically known as spermatozoa, which are able to fertilize the counterpart female gamete, the oocyte, during conception to produce a single-celled individual known as a zygote. This is the cornerstone of sexual reproduction and involves the two gametes both contributing half the normal set of chromosomes (haploid) to result in a chromosomally normal (diploid) zygote.

To preserve the number of chromosomes in the offspring – which differs between species – each gamete must have half the usual number of chromosomes present in other body cells. Otherwise, the offspring will have twice the normal number of chromosomes, and serious abnormalities may result. In humans, chromosomal abnormalities arising from incorrect spermatogenesis results in congenital defects and abnormal birth defects (Down Syndrome, Klinefelter's Syndrome) and in most cases, spontaneous abortion of the developing fetus.

Location

Spermatogenesis takes place within several structures of the male reproductive system. The initial stages occur within the testes and progress to the epididymis where the developing gametes mature and are stored until ejaculation. The seminiferous tubules of the testes are the starting point for the process, where stem cells adjacent to the inner tubule wall divide in a centripetal direction—beginning at the walls and proceeding into the innermost part, or lumen—to produce immature sperm. Maturation occurs in the epididymis. The location [Testes/Scrotum] is specifically important as the process of spermatogenesis requires a lower temperature to produce viable sperm, specifically 1°-8 °C lower than normal body temperature of 37 °C (98.6 °F).[3] Clinically, small fluctuations in temperature such as from an athletic support strap, causes no impairment in sperm viability or count.[4]

Duration

For humans, the entire process of spermatogenesis is variously estimated as taking 74 days[5][6] (according to tritium-labelled biopsies) and approximately 120 days[7] (according to DNA clock measurements). Including the transport on ductal system, it takes 3 months. Testes produce 200 to 300 million spermatozoa daily.[8] However, only about half or 100 million of these become viable sperm.[9]

Stages

The entire process of spermatogenesis can be broken up into several distinct stages, each corresponding to a particular type of cell in human. In the following table, ploidy, copy number and chromosome/chromatid counts are for one cell, generally prior to DNA synthesis and division (in G1 if applicable). The primary spermatocyte is arrested after DNA synthesis and prior to division.

Cell type ploidy/chromosomes in human DNA copy number/chromatids in human Process entered by cell
spermatogonium (types Ad, Ap and B) diploid (2N) / 46 2C / 46 spermatocytogenesis (mitosis)
primary spermatocyte diploid (2N) / 46 4C / 2x46 spermatidogenesis (meiosis I)
two secondary spermatocytes haploid (N) / 23 2C / 2x23 spermatidogenesis (meiosis II)
four spermatids haploid (N) / 23 C / 23 spermiogenesis
four functional spermatozoids haploid (N) / 23 C / 23 spermiation

Spermatocytogenesis

Main article: Spermatocytogenesis
The process of spermatogenesis as the cells progress from primary spermatocytes, to secondary spermatocytes, to spermatids, to Sperm
Schematic diagram of Spermatocytogenesis

Spermatocytogenesis is the male form of gametocytogenesis and results in the formation of spermatocytes possessing half the normal complement of genetic material. In spermatocytogenesis, a diploid spermatogonium, which resides in the basal compartment of the seminiferous tubules, divides mitotically, producing two diploid intermediate cells called primary spermatocytes. Each primary spermatocyte then moves into the adluminal compartment of the seminiferous tubules and duplicates its DNA and subsequently undergoes meiosis I to produce two haploid secondary spermatocytes, which will later divide once more into haploid spermatids. This division implicates sources of genetic variation, such as random inclusion of either parental chromosomes, and chromosomal crossover, to increase the genetic variability of the gamete.

Each cell division from a spermatogonium to a spermatid is incomplete; the cells remain connected to one another by bridges of cytoplasm to allow synchronous development. It should also be noted that not all spermatogonia divide to produce spermatocytes; otherwise, the supply of spermatogonia would run out. Instead, certain types of spermatogonia divide mitotically to produce copies of themselves, ensuring a constant supply of spermatogonia to fuel spermatogenesis.[10]

Spermatidogenesis

Main article: Spermatidogenesis

Spermatidogenesis is the creation of spermatids from secondary spermatocytes. Secondary spermatocytes produced earlier rapidly enter meiosis II and divide to produce haploid spermatids. The brevity of this stage means that secondary spermatocytes are rarely seen in histological studies.

Spermiogenesis

Main article: Spermiogenesis

During spermiogenesis, the spermatids begin to form a tail by growing microtubules on one of the centrioles, which turns into basal body. These microtubules form an axoneme. The anterior part of the tail (called midpiece) thickens because mitochondria are arranged around the axoneme to ensure energy supply. Spermatid DNA also undergoes packaging, becoming highly condensed. The DNA is packaged firstly with specific nuclear basic proteins, which are subsequently replaced with protamines during spermatid elongation. The resultant tightly packed chromatin is transcriptionally inactive. The Golgi apparatus surrounds the now condensed nucleus, becoming the acrosome.

Maturation then takes place under the influence of testosterone, which removes the remaining unnecessary cytoplasm and organelles. The excess cytoplasm, known as residual bodies, is phagocytosed by surrounding Sertoli cells in the testes. The resulting spermatozoa are now mature but lack motility, rendering them sterile. The mature spermatozoa are released from the protective Sertoli cells into the lumen of the seminiferous tubule in a process called spermiation.

The non-motile spermatozoa are transported to the epididymis in testicular fluid secreted by the Sertoli cells with the aid of peristaltic contraction. While in the epididymis the spermatozoa gain motility and become capable of fertilization. However, transport of the mature spermatozoa through the remainder of the male reproductive system is achieved via muscle contraction rather than the spermatozoon's recently acquired motility.

Role of Sertoli cells

Labelled diagram of the organisation of Sertoli cells (red) and spermatocytes (blue) in the testis. Spermatids which have not yet undergone spermination are attached to the lumenal apex of the cell
Main article: Sertoli cell

At all stages of differentiation, the spermatogenic cells are in close contact with Sertoli cells which are thought to provide structural and metabolic support to the developing sperm cells. A single Sertoli cell extends from the basement membrane to the lumen of the seminiferous tubule, although the cytoplasmic processes are difficult to distinguish at the light microscopic level.

Sertoli cells serve a number of functions during spermatogenesis, they support the developing gametes in the following ways:

The intercellular adhesion molecules ICAM-1 and soluble ICAM-1 have antagonistic effects on the tight junctions forming the blood-testis barrier.[12] ICAM-2 molecules regulate spermatid adhesion on the apical side of the barrier (towards the lumen).[12]

Influencing factors

The process of spermatogenesis is highly sensitive to fluctuations in the environment, particularly hormones and temperature. Testosterone is required in large local concentrations to maintain the process, which is achieved via the binding of testosterone by androgen binding protein present in the seminiferous tubules. Testosterone is produced by interstitial cells, also known as Leydig cells, which reside adjacent to the seminiferous tubules.

Seminiferous epithelium is sensitive to elevated temperature in humans and some other species, and will be adversely affected by temperatures as high as normal body temperature. Consequently, the testes are located outside the body in a sack of skin called the scrotum. The optimal temperature is maintained at 2 °C (man)–8 °C (mouse) below body temperature. This is achieved by regulation of blood flow[13] and positioning towards and away from the heat of the body by the cremasteric muscle and the dartos smooth muscle in the scrotum.

Dietary deficiencies (such as vitamins B, E and A), anabolic steroids, metals (cadmium and lead), x-ray exposure, dioxin, alcohol, and infectious diseases will also adversely affect the rate of spermatogenesis. In addition, the male germ line is susceptible to DNA damage caused by oxidative stress, and this damage likely has a significant impact on fertilization and pregnancy.[14] Exposure to pesticides also affects spermatogenesis.[15]

Hormonal control

Hormonal control of spermatogenesis varies among species. In humans the mechanism is not completely understood; however it is known that initiation of spermatogenesis occurs at puberty due to the interaction of the hypothalamus, pituitary gland and Leydig cells. If the pituitary gland is removed, spermatogenesis can still be initiated by follicle stimulating hormone (FSH) and testosterone.[16] In contrast to FSH, LH appears to have little role in spermatogenesis outside of inducing gonadal testosterone production.[16][17]

FSH stimulates both the production of androgen binding protein (ABP) by Sertoli cells, and the formation of the blood-testis barrier. ABP is essential to concentrating testosterone in levels high enough to initiate and maintain spermatogenesis. Intratesticular testosterone levels are 20–100 or 50–200 times higher than the concentration found in blood, although there is variation over a 5- to 10-fold range amongst healthy men.[18][19] FSH may initiate the sequestering of testosterone in the testes, but once developed only testosterone is required to maintain spermatogenesis.[16] However, increasing the levels of FSH will increase the production of spermatozoa by preventing the apoptosis of type A spermatogonia. The hormone inhibin acts to decrease the levels of FSH. Studies from rodent models suggest that gonadotropins (both LH and FSH) support the process of spermatogenesis by suppressing the proapoptotic signals and therefore promote spermatogenic cell survival.[20]

The Sertoli cells themselves mediate parts of spermatogenesis through hormone production. They are capable of producing the hormones estradiol and inhibin. The Leydig cells are also capable of producing estradiol in addition to their main product testosterone. Estrogen has been found to be essential for spermatogenesis in animals.[21][22] However, a man with estrogen insensitivity syndrome (a defective ERα) was found produce sperm with a normal sperm count, albeit abnormally low sperm viability; whether he was sterile or not is unclear.[23] Levels of estrogen that are too high can be detrimental to spermatogenesis due to suppression of gonadotropin secretion and by extension intratesticular testosterone production.[24] Prolactin also appears to be important for spermatogenesis.[17]

See also

References

  1. ↑ "The Spermatozoön, in Gray's Anatomy". Retrieved 2010-10-07.
  2. ↑ Song, Ning; Liu, Jie; An, Shucai; Nishino, Tomoya; Hishikawa, Yoshitaka; Koji, Takehiko (2011). "Immunohistochemical Analysis of Histone H3 Modifications in Germ Cells during Mouse Spermatogenesis". Acta Histochemica et Cytochemica 44 (4): 183–90. doi:10.1267/ahc.11027. PMC 3168764. PMID 21927517.
  3. ↑ "scrotum". Encyclopædia Britannica. Encyclopædia Britannica Online. Encyclopædia Britannica Inc., 2015. Web. 14 Jan. 2015 <http://www.britannica.com/EBchecked/topic/530078/scrotum>.
  4. ↑ Wang C, McDonald V, Leung A, Superlano L, Berman N, Hull L, Swerdloff RS (1997). "Effect of increased scrotal temperature on sperm production in normal men". Fertil. Steril. 68 (2): 334–9. doi:10.1016/s0015-0282(97)81525-7. PMID 9240266.
  5. ↑ Heller CG, Clermont Y (1964). "Kinetics of the germinal epithelium in man". Recent Prog Horm Res 20: 545–571.
  6. ↑ Amann RP (2008). "The cycle of the seminiferous epithelium in humans: a need to revisit?". J Androl 29 (5): 469–487. doi:10.2164/jandrol.107.004655. PMID 18497337.
  7. ↑ Forster P, Hohoff C, Dunkelmann B, Schürenkamp M, Pfeiffer H, Neuhuber F, Brinkmann B (2015). "Elevated germline mutation rate in teenage fathers". Proc R Soc B 282: 20142898. doi:10.1098/rspb.2014.2898. PMC 4345458. PMID 25694621.
  8. ↑ Padubidri, VG; Daftary, SN, eds. (2011). Shaw's Textbook of Gynaecology (15th ed.). p. 201. ISBN 978-81-312-2548-6.
  9. ↑ Johnson L, Petty CS, Neaves WB (1983). "Further quantification of human spermatogenesis: germ cell loss during postprophase of meiosis and its relationship to daily sperm production". Biol. Reprod. 29 (1): 207–15. doi:10.1095/biolreprod29.1.207. PMID 6615966.
  10. ↑ Fishelson, Lev; Gon, Ofer; Holdengreber, Vered; Delarea, Yakob (2007). "Comparative spermatogenesis, spermatocytogenesis, and spermato-zeugmata formation in males of viviparous species of clinid fishes (Teleostei: Clinidae, Blennioidei)". The Anatomical Record 290 (3): 311–23. doi:10.1002/ar.20412. PMID 17525946.
  11. ↑ Hadley, Mac E.; Levine, Jon E. (2007). Endocrinology (6th ed.). Upper Saddle River, NJ: Prentice Hall. p. 369. ISBN 0-13-187606-6.
  12. 1 2 Xiao, X.; Mruk, D. D.; Cheng, C. Y. (2013). "Intercellular adhesion molecules (ICAMs) and spermatogenesis". Human Reproduction Update 19 (2): 167–86. doi:10.1093/humupd/dms049. PMC 3576004. PMID 23287428.
  13. ↑ Harrison, RG; Weiner, JS (1949). "Vascular patterns of the mammalian testis and their functional significance". The Journal of Experimental Biology 26 (3): 304–16, 2 pl. PMID 15407652.
  14. ↑ Lewis, SE; Aitken, RJ (2005). "DNA damage to spermatozoa has impacts on fertilization and pregnancy". Cell and tissue research 322 (1): 33–41. doi:10.1007/s00441-005-1097-5. PMID 15912407.
  15. ↑ Mehrpour, O; Karrari P (2014). "Occupational exposure to pesticides and consequences on male semen and fertility: A review.". Toxicol Lett 230: 146–156. doi:10.1016/j.toxlet.2014.01.029. PMID 24487096.
  16. 1 2 3 William J. Kraemer; A. D. Rogol (15 April 2008). The Encyclopaedia of Sports Medicine: An IOC Medical Commission Publication, The Endocrine System in Sports and Exercise. John Wiley & Sons. pp. 286–. ISBN 978-0-470-75780-2.
  17. 1 2 Fody EP, Walker EM (1985). "Effects of drugs on the male and female reproductive systems". Ann. Clin. Lab. Sci. 15 (6): 451–8. PMID 4062226.
  18. ↑ Wolf-Bernhard Schill; Frank H. Comhaire; Timothy B. Hargreave (26 August 2006). Andrology for the Clinician. Springer Science & Business Media. pp. 76–. ISBN 978-3-540-33713-3.
  19. ↑ Eberhard Nieschlag; Hermann M. Behre; Susan Nieschlag (26 July 2012). Testosterone: Action, Deficiency, Substitution. Cambridge University Press. pp. 130–. ISBN 978-1-107-01290-5.
  20. ↑ Pareek, Tej K.; Joshi, Ayesha R.; Sanyal, Amartya; Dighe, Rajan R. (2007). "Insights into male germ cell apoptosis due to depletion of gonadotropins caused by GnRH antagonists". Apoptosis 12 (6): 1085–100. doi:10.1007/s10495-006-0039-3. PMID 17268770.
  21. ↑ O'Donnell L, Robertson KM, Jones ME, Simpson ER (2001). "Estrogen and spermatogenesis". Endocr. Rev. 22 (3): 289–318. doi:10.1210/edrv.22.3.0431. PMID 11399746.
  22. ↑ Carreau S, Bouraima-Lelong H, Delalande C (2012). "Role of estrogens in spermatogenesis". Front Biosci (Elite Ed) 4: 1–11. PMID 22201851.
  23. ↑ Smith, Eric P.; Boyd, Jeff; Frank, Graeme R.; Takahashi, Hiroyuki; Cohen, Robert M.; Specker, Bonny; Williams, Timothy C.; Lubahn, Dennis B.; Korach, Kenneth S. (1994). "Estrogen Resistance Caused by a Mutation in the Estrogen-Receptor Gene in a Man". New England Journal of Medicine 331 (16): 1056–1061. doi:10.1056/NEJM199410203311604. ISSN 0028-4793.
  24. ↑ Edmund S. Sabanegh, Jr. (20 October 2010). Male Infertility: Problems and Solutions. Springer Science & Business Media. pp. 83–. ISBN 978-1-60761-193-6.

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