Testis

The testis is a mass of seminiferous tubules, interstitial cells, and blood vessels encased in a connective tissue sheath.

From: Herpetology (Third Edition), 2009

Reproductive and Endocrine Toxicology

E.W.P. Wong, ... C.Y. Cheng, in Comprehensive Toxicology, 2010

11.09.2.3.2 Physiological significance of the BTB and its vulnerability to cadmium toxicity

In mammalian testis, BTB anatomically divides the seminiferous epithelium into the basal and the adluminal compartments. During spermatogenesis, preleptotene spermatocytes residing in the basal compartment of the seminiferous epithelium must translocate across the BTB, entering into the adluminal compartment for further development at stage VIII of the epithelial cycle (Russell 1977). Once behind the BTB, spermatocytes continue their differentiation into spermatids and migrate progressively across the epithelium until elongated spermatids reach the luminal edge of the epithelium (de Kretser 1990; de Kretser and Kerr 1988). The fully developed elongated spermatids (spermatozoa) then detach from the epithelium at late stage VIII of the epithelial cycle at spermiation. This event of germ cell movement across the BTB is undoubtedly unique to the testis. It also illustrates that BTB is a highly dynamic structure since it has to open (or restructure) to facilitate germ cell migration while maintaining the barrier function to sequester postmeiotic germ cell antigens behind the BTB from the immune system of the host animal (for reviews, see Byers et al. (1993), de Kretser and Kerr (1988), Dym and Cavicchia (1978), Dym and Fawcett (1970), Pelletier (2001), and Pelletier and Byers (1992)). It is likely that due to the dynamic nature of the BTB, it is being safeguarded by the coexisting TJ and specialized AJ structures basal ES. This is plausibly physiologically necessary, perhaps even essential, to maintain BTB integrity during extensive junction restructuring in the seminiferous epithelium pertinent to spermatogenesis. Yet it is also plausible that because of this unusual feature of the BTB being composed of coexisting AJs and TJs, it makes the BTB more susceptible to cadmium toxicity. For instance, it is known that cadmium mediates its toxic effects primarily on AJ proteins (e.g., E-cadherin) (Prozialeck 2000), perhaps only secondarily on TJ proteins and cytoskeletal elements. But since the BTB is composed of coexisting TJ and AJ proteins and the BTB is adjacent to ECM in close proximity to the interstitium, basal ES proteins (e.g., E-cadherin and integrins) at the BTB are readily exposed to cadmium. As such, BTB is more severely affected by cadmium than microvascular TJ barrier where TJ proteins are restricted to the apical surface which, in turn, seals the underlying AJ network from cadmium.

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Urinary System, Genital Systems, and Reproduction

Bruno Cozzi, ... Helmut Oelschläger, in Anatomy of Dolphins, 2017

The Testes and Epididymis

The testes of dolphins are located within the abdominal cavityu (Fig. 9.41). The testes of cetaceans are comparatively larger in respect to body mass than in most terrestrial mammals (Kenagy and Trombulak, 1986; Aguilar and Monzon, 1992).

Figure 9.41. Testes of T. truncatus in place.

The testes do not have the common ovoid aspects typical of several terrestrial mammals, including man. The gonads of dolphins are rather long cylinders (Fig. 9.42), with slender extremities, and can be examined in vivo using ultrasound technology (Fig. 9.43). The epididymis surrounds the testis for all its length and is more conspicuous at the two poles. The cranial pole of the testes is connected to the caput of the epididymis, and the caudal pole to its tail. The epididymis is in fact made up by long network of continuous tubes, whose total length may easily reach tens of meters.v There are no references on the length of the epididymis in dolphins. Testicular veins are well evident through the translucent tunica albuginea of the gonads (Fig. 9.44).

Figure 9.42. Testicle and epididymis of T. truncatus.

Figure 9.43. Ultrasound image of the testicle of a young adult bottlenose dolphin.

Courtesy of Pietro Saviano.

Figure 9.44. Testicular veins of T. truncatus seen throughout the tunica albuginea.

Size of the testes in the bottlenose dolphin varies from 4.4 to a maximum of 22.8 cm, and volume from 4 to 531 cm3 (Brook et al., 2000), depending on age and body dimensions (Table 9.7). In the Pacific white-sided dolphin (L. obliquidens) the size of the testes varies according to the season, being larger during July and August, approximately corresponding to testosterone peaks (see later) and the onset of reproductive activities (Robeck et al., 2009).

Table 9.7. Dimensions of the Testes in the Bottlenose Dolphin Based on Ultrasonography (Brook et al., 2000)

Maturity StageDimensions (cm)Volume (cm3)Ultrasonography Notes
Immature males4.4–6.44–4.6Poorly differentiated
Markedly hypoechoic in relation to the m. hypaxialis lumborum
Subadult males8.8–15.910.3–45.7Homogeneous echopattern
Less echogenic than the m. hypaxialis lumborum
Mature males14–22.8147–531Mid- to high-level intensity; isoechoic or slightly hyperechoic compared to the m. hypaxialis lumborum

Structure

The testes of dolphins have the typical structure of the testes of all mammals (Figs. 9.45 and 9.46). The testicular parenchyma is made up by seminiferous tubules and by islets of tissue among the tubules. Seminiferous tubules contain Sertoli cells and germinal cells at various stages of maturationw: spermatogonia, spermatocytes, spermatids and spermatozooax (see also Section “Spermatogenesis, Sexual Maturity, and Seasonality”). During fetal development, Sertoli cells are responsible for the regression of the paramesonefric ducts (the anlage of female genital organs), by secreting the Anti-Müllerian Hormone (AMH, a glycoprotein). However, there are no specific descriptions of AMH in dolphins or other cetacean species.

Figure 9.45. Microphotograph of the testes of T. truncatus (scale bar = 50 μm).

HE stain.

Figure 9.46. Testicle of G. griseus (scale bar = 500 μm).

HE stain.

The intertubular islets contain the interstitial cells (also called Leydig cells) that are responsible for the productions of testosterone (see later for notes on male reproductive physiology). The interstitial cells of dolphins are generally more slender if compared to those of terrestrial mammals, and contain no pigment. They are less conspicuous than in other mammals, and their presence is somewhat difficult to detect (Simpson and Gardner, 1972). They may be grouped together in few (but not all) of the spaces between adjacent tubules.

In T. truncatus aduncus, the diameter of the tubules in the epididymis was determined by ultrasonography to be between 2–3 and even 3–5 mm at the caudal pole (Brook et al., 2000). In the same study, the diameter of the tubules decreased considerably (up to 2 mm) following ejaculation.

Temperature

Temperature is a key factor for the maturation of spermatozoa, and one of main reasons why in most mammals the testes are outside the body cavity (at least during the reproductive season). A temperature of 37°C may be fatal for proper maturation and lead to infertility or even cause pathologies. As already outlined, the testes of dolphins are placed inside the peritoneal cavity and reduction of their temperature is essential. As for the ovary, a specific vascular plexus provides counter-exchange cooling of the blood that reaches the gonads (Rommel et al., 1992, 1994, 1998). Contrarily to terrestrial mammals, there is no single testicular artery, but there are 20–40 arteries vessels leaving the aorta towards the testicles (TAP, or testicular arterial plexus). They form a comb of parallel arteries that surround the testicle and then coalesce into a single artery that enters the organ from the caudal pole (Rommel et al., 2007). Venous drainage occurs through the testicular venous plexus (TVP) that drains blood into the caudal vena cava. TAP and TVP are encompassed by two layers of the peritoneum corresponding to the mesorchium of terrestrial mammals (Rommel et al., 2007). Heat exchange takes place by the lumbocaudal venous plexus (LCVP), formed by thin-walled veins and located ventrally to the hypaxial muscles. LCVP is supplied with blood that derives from the flukes and the dorsal fin, and is therefore cooler than that bound to (or returning from) the gonads (Pabst et al., 1995). LCVP is drained by the caudal vena cava.

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Reproductive System, Male

R.E. Chapin, in Encyclopedia of Toxicology (Third Edition), 2014

Testicular (Non–Germ Cell) Targets

The testes are specialized for the development of germ cells into spermatozoa and the production of testosterone. The two major non–germ cell types supporting these functions are the Sertoli cell and the Leydig cell, with additional important roles played by the peritubular cells (which surround the outside of each tubule) and the vasculature and lymphoid cells. Various agents that target the Sertoli or Leydig cells can disrupt spermatogenesis directly by affecting cell function or indirectly by interfering with the hormonal regulation of spermatogenesis, respectively. Because these somatic cells are integral to the processes of spermatogenesis, each could be considered as a potential target of toxicants, although this has only been documented for the Leydig cells and the Sertoli cells.

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The brain-pituitary-gonad axis and the gametogenesis

Maria Inês Borella, ... Sergio Ricardo Batlouni, in Biology and Physiology of Freshwater Neotropical Fish, 2020

Morphology of testis

The testis of fish is generally a paired organ, elongated, and enveloped by the albuginea, a capsule of connective tissue. Reflecting several reproductive strategies and different stages of the gonadal cycle, the testes of fish can show variations in size, weight, color, and shape.

Among the South American teleost fish, the majority show smooth testes,such as A. altiparanae (Costa et al., 2014). However, the fish belonging to the Siluriform group generally show a great number of fringes, such as can be observed in Iheringichthys labrusus (Santos et al., 2001), P. fasciatum (Batlouni et al., 2006), and Lophiosilurus alexandri (Barros et al., 2007).

Concerning the organization of the seminiferous tubule, the testis of fish can be classified as anastomosing tubule testis or lobular testis. In the anastomosing tubular type, the seminiferous tubule interconnects, forming a highly branched and anastomosing network. The lobular type has a seminiferous tubule that terminates blindly in the periphery of the organ, below the albuginea tunica. It can be divided into two subtypes, the spermatogonial unrestricted and the spermatogonial restricted type. The spermatogonial unrestricted type is characterized by the presence of spermatogonia along all the lobules. On the other hand, the spermatogonial restricted type has the spermatogonia only in the distal part of the tubule, located near the albuginea tunica area (Grier, 2002).

Nevertheless, in the literature, different forms of descriptions of the testis of fish can be found. For example, Vicentini et al. (2002) show the morphology and the ultrastructure of the testis of P. scrofa, describing that the seminiferous tubule of this species is anastomosed and has an unrestricted distribution of spermatogonia along the germinative epithelium.

The histological analysis of fish testis as well as in other vertebrates allows recognizing two compartments: the germinative epithelium and the interstitial compartment, separated by a basement membrane (Grier, 2002). In the germinative compartment, two groups of cells can be seen: the germ cells and the Sertoli cells. When the Sertoli cells envelop the germ cells, they form the cysts. The interstitial compartment is composed of cells of the connective tissue, smooth muscular fibers, Leydig cells, and peritubular myoid cells.

Costa et al. (2014) demonstrated that, in A. altiparanae, the Sertoli cells, besides supporting the germ cells, play another role and acquire a secretory function. These authors showed that at the beginning of the reproductive cycle of A. altiparanae, the Sertoli cells support spermatogonia and the other germ cells. After the release of spermatids, the Sertoli cells undergo changes in their shape and promote a secretory function (Fig. 14.5).

Myoid peritubular cells are found below the basement membrane of the germinative epithelium. These cells are elongated and have contractile activity, which helps in the displacement mass of spermatozoa along the tubule lumen. Additional functions have been proposed for the myoid peritubular cells of mammalians, such as the production of the extracellular matrix compounds, secretion of growth factors, and participation of the hematotesticular barrier. In fish, other functions of these cells are yet unknown.

The Leydig cells (Fig. 14.5) are involved in the synthesis of steroid hormones, a function that is better studied in the mammalian testis. In fish, the Leydig cells are found in the angular interstitium, that is, in areas not occupied by the seminiferous tubules, where the interstitial tissue is larger. Nóbrega and Quagio-Grassioto (2007) demonstrated the presence of the 3β-HSD enzyme in the Leydig cells of S. spilopleura. This enzyme is essential to the biosynthesis of steroid hormones, which corroborates the attribution of steroidogenic function to these cells in fish.

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The endocrinology of mammalian reproduction

David O. Norris PhD, James A. Carr PhD, in Vertebrate Endocrinology (Sixth Edition), 2021

The testes are considered an “immune privileged” organ because they produce a number of chemical signals that protect cells of the spermatogenetic lineage from being recognized as being foreign by cells of the immune system. Sertoli cells modulate the activity of local white blood cells by secreting cytocrines that act in a paracrine fashion to influence resident macrophage cells in the testis (Box Fig. 10E.1). The ability of Sertoli cells to modulate immune cells holds promise for organ transplant technology. For example, Sertoli cells protect pancreatic islet implants from being attacked by the host’s immune system. Coimplantation of Sertoli cells with pancreatic islets represents a promising treatment for type 1 diabetes.

Box Figure 10E.1. Chemical signals involved in the immune network of the testes. The immune cell cohort of the testis includes macrophages, natural killer lymphocytes (NKs), T lymphocytes (T), and dendritic cells (DCs) that aid in antigen presentation to lymphocytes and macrophages. In the process of phagocytosing residual cellular material from developing sperm, Sertoli cells generate potential antigens to be recognized by the immune cells. To prevent the immune system from attacking developing sperm cells, adaptive immunity pathways mediated via T lymphocytes are suppressed, whereas innate immunity via NK cells is enhanced through signaling from transforming growth factor β (TGFβ), activin, and interleukin-10 (IL-10). Failure to keep adaptive immunity pathways in check will lead to T cells attacking spermatogenetic cells and infertility.

Adapted with permission from Meinhardt, A., Hedger, M.P., 2011. Molecular and Cellular Endocrinology 335, 60–68.
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Vulnerable Patients

Rosalind Dalefield BVSc PhD DABVT DABT, in Veterinary Toxicology for Australia and New Zealand, 2017

The Stud Male

The testes of the adult male animal are partially protected from circulating xenobiotics by the blood–testis barrier. This barrier is formed by myoid cells and by tight junctions between Sertoli cells. Leydig cells are outside this barrier and may be harmed by xenobiotics that do not reach the seminiferous tubules.

Deleterious effects on male reproduction are not confined to those that act directly on the testes, but include those that interfere with normal male endocrinology, such as exposure to estrogenic compounds, and those that affect the physical ability to mate, such as skeletal effects of fluorosis in cattle or hypervitaminosis A in the cat.

Any xenobiotic that causes pyrexia (e.g., phenoxy herbicides) or which interferes with cellular replication (e.g., chemotherapeutics) may cause a decline in spermatogenesis. This may be reversible once the xenobiotic has been largely metabolized and/or excreted, provided the spermatogonia are not harmed.

The length of the spermatogenic process varies between species, and this should be borne in mind when choosing the time to test the sperm count of a stud male to determine if recovery from toxic effects of a xenobiotic has occurred. The estimated length of the spermatogenic cycle for the common domestic species is summarized in Table 5.1.

Table 5.1. Estimated Duration of the Spermatogenic Process in Males of the Common Domestic Species

SpeciesDuration (days)
Horse57
Bull56–63
Ram46–49
Goat48
Boar36–40
Dog62
Cat47

Veterinary therapeutics known to have deleterious effects on male reproductive function are listed in Table 5.2. Some environmental xenobiotics that are known to have deleterious effects on male reproductive function are listed in Table 5.3. These lists are not exhaustive, and if there is any question of the safety of a chemical to the reproductive abilities of a stud animal, further information should be sought from a pharmacopeia, Materials Safety Data Sheet, or chemical databank, as appropriate.

Table 5.2. Veterinary Therapeutics Known to Have Deleterious Effects on Male Reproductive Function of Mammals

Type or Use of XenobioticXenobioticEffect/s
HormonesTestosteroneDoses in excess of physiological levels cause decreased sperm count, testicular degeneration
Anabolic steroids (including zeranol)Decreased sperm count and motility, morphological changes in sperm
EstrogensDecreased sperm count, feminization of behavior
ProgestinsDecreased sperm count and quality
ProlactinDecreased sperm count, testicular degeneration
TrenboloneDecreased sperm quality
AntibioticsMetronidazoleDecreased sperm count, morphological changes in sperm
NitrofurantoinDecreased sperm count
TetracyclineDecreased sperm count, testicular degeneration
TrimethoprimDecreased sperm count
AntifungalKetoconazoleDecreased testosterone levels and libido
Decreased sperm count and motility
ChemotherapeuticsAdriamycinTesticular degeneration
CisplatinDecreased sperm count
CyclophosphamideDecreased sperm count
CytarabineDecreased sperm count
VincristineDecreased sperm count (may be persistent)
AntiparasiticBunamidineInterference with spermatogenesis
DiureticAcetazolamideDecreased libido, impotence
Behavioral modificationBuspironeDecreased libido, impotence
BenzodiazepinesDecreased libido, impotence
PhenothiazinesPriapism, impotence
Tricyclic antidepressantsDecreased libido, impotence
AntacidCimetidineDecreased prostaglandins in semen
AntiemeticMetaclopramideImpotence
Nonsteroidal antiinflammatoriesSulfasalazineDecreased sperm count and motility
GlucocorticoidsPrednisoneDecreased sperm count and motility, decreased testosterone levels
AnestheticsThiamylalDecreased testosterone levels

Table 5.3. Some Environmental Xenobiotics Known to Have Deleterious Effects on Male Reproductive Function of Mammals

Type or Use of XenobioticXenobioticEffect/s
MetalsCadmiumIschemic necrosis of the testis
LeadDecreased sperm count and testosterone levels
ChromiumDecreased sperm count and quality; decreased testosterone levels
MercuryDecreased sperm quality
InsecticidesCarbamatesDecreased sperm quality
PyrethrinsCompetitively bind to androgen receptors; in vivo impact unclear
HerbicidesDichlorophenoxyacetic acidDecreased sperm quality, testicular degeneration
FungicidesVinclozolinAndrogen receptor antagonist
NematocidesDibromochloropropaneDecreased sperm count
AntifreezeEthylene glycolDecreased sperm count and motility
Recreational drugsMarijuanaDecreased sperm count and testosterone levels
TobaccoDecreased sperm count
Food additivesCyclamateA metabolite, cyclohexylamine, is toxic to the testes
PhytoestrogensSoy phytoestrogens may act as estrogens in stud cats
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Class Ostracoda

Alison J. Smith, ... Isa Schön, in Thorp and Covich's Freshwater Invertebrates (Fourth Edition), 2015

Male Reproductive Structures

The testes are similarly placed in males as the ovaries in females, and traces of them can be seen on the inner and posterior region of the shell, as in the Candoninae (Figure 30.8). In some groups, such as the Cypricercinae (e.g., Bradleystrandesia), the testes form a spiral around the inner edge of the shell rather than being confined to the posterior area. The testes change into the vasa deferentia as they leave the epidermis and enter the body cavity. The vas deferens joins up with the ejaculation ducts or, in the case of the Cypridoidea, Zenker’s Organs. (Figure 30.9). These large organs are made up of longitudinal as well as radial muscles in the shape of a tube, on which are found radiating bristles covered in a chitinous sheath. The alternate contraction and expansion of these paired organs pump the sperm into the hemipenes during copulation. Zenker’s organs lie in a nearly horizontal position in the posterior part of the body cavity and are visible through transparent shells in many live specimens. Zenker’s organs are absent in the Cytheroidea, where part of the hemipenis itself performs the function of a sperm pump, and in the Darwinulidae, which might indicate that the exceptionally rare males in this latter group are nonfunctional (Smith et al., 2006).

The spermatozoa of ostracodes are among the largest produced in the animal kingdom (exceeded only by certain species of Drosophila (Pitnick and Marcow, 1994) and, in many cases, greatly exceed the length of the ostracode carapace (see Matzke-Karasz, 2005 and references therein). For example, Meisch (2000) reported that for Cyclocypris ovum (Jurine, 1820) (carapace length of 0.5–0.7 mm), the sperm length is 6 mm, approximately 10 times the length of the animal! For males, the production and presentation of such large sperm requires extensive coiling of the testes to fit them within the carapace. In transmitted light, the sperm are often visible within the female seminal receptacle and are identifiable by a spiraled coiled line (Matzke-Karasz, 2005). Both hemipenes function during copulation, and multiple sperm are delivered into the female receptacle (see below), as has been observed by Vandekerkhove et al. (2007) in dissections of Eucypris virens (Jurine, 1820).

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Reproductive System, Male

Marion G. Miller, Shelley Brown DuTeaux, in Encyclopedia of Toxicology (Second Edition), 2005

Physiology of the Male Reproductive System

A series of tightly orchestrated events must occur for a male to produce viable sperm capable of fertilization and producing normal offspring (Figure 1). The process of spermatogenesis in the testis is subject to neuroendocrine controls via the hypothalamic-pituitary axis (I), and indirect influences arising from nutritional status, liver metabolism, and vascularization (II). Within the testis (III), endocrine, autocrine, and paracrine controls are required for the proliferation and differentiation of the stem cell spermatogonia into the mature spermatid that is released into the lumen of the seminiferous tubule. The released spermatozoa travel through the rete testis and efferent ducts to the head (caput) of the epididymis. As the spermatozoa pass through the middle (corpus) and tail (cauda) of the epididymis, they undergo maturation (IV) and gain motility as well as the ability to fertilize oocytes. Toxicants could affect any of these steps or have direct effects on sperm cell viability (V) or on the ability to penetrate and fertilize an oocyte (VI). To date, little is known about male mediated developmental toxicity, whereby the male gamete transmits inheritable defects to offspring (VII). This possibility has received more attention in recent years.

Figure 1. Overview of the male reproductive system.

The Testis and Spermatogenesis

The testis is made up of tightly packed seminiferous tubules surrounded by a vascularized interstitium. It is enclosed in a tough fibrous capsule called the tunica albuginea (Figure 2). Within the seminiferous tubules, germ cells develop into spermatozoa in a process called spermatogenesis. The Leydig cells located between tubules in the testis interstitium carry out the synthesis of steroids. Steroidogenesis is essential both for spermatogenesis and for developing and maintaining secondary sexual characteristics. (For more about steroids, see section ‘Hypothalamic–Pituitary–Gonadal Axis’.)

Figure 2. Schematic representation of the structure of the testis. (Reproduced from Working PK (1989) Toxicology of the Male and Female Reproductive Systems. New York: Hemisphere, with permission from Taylor and Francis, Inc.)

The production of gametes in mammals (spermatogenesis, oogenesis) requires the process of meiosis to reduce the number of chromosomes in each cell from 46 (diploid) to 23 (haploid) so that a fertilized zygote will contain 46 chromosomes, half from each parent. In the male, the process of spermatogenesis involves mitosis and meiosis and three germ cell types: (1) spermatogonia, (2) spermatocytes in various stages of meiosis, and (3) postmeiotic spermatids undergoing elongation prior to release as spermatozoa. The first germ cell type, spermatogonia, undergo stepwise mitotic proliferation and differentiation and are classified by their stage of development (types A1–A4, intermediate, and type B). Type B spermatogonia ultimately divide into primary spermatocytes that enter meiosis. The process of reducing chromosomes from 46 in diploid spermatocytes to 23 in haploid spermatids starts in the preleptotene phase of meiosis I. Each primary spermatocyte enters meiotic prophase, forming distinct cell types at each phase (leptotene, zygotene, pachytene, and diplotene). At the end of meiosis I, two secondary spermatocytes are produced which enter meiosis II and rapidly divide to produce a total of four haploid round spermatids with 23 chromosomes each.

The metamorphosis of round spermatids into spermatozoa is described as spermiogenesis. Initially, the round spermatid develops an acrosome derived from the intracellular Golgi complex. The acrosome starts as a small vesicle and develops into a pronounced cap on the sperm head. The acrosome is necessary for oocyte fertilization and contains the lysosomal enzymes required to penetrate the vestments surrounding the egg. Early in spermiogenesis, a microtubule-containing flagellum begins to develop. Nuclear DNA undergoes condensation and is no longer synthesized before the nuclei elongate around a microtubule structure called the manchette. As the spermatid elongates, mitochondria collect in a sheath behind the sperm head and around the flagellum in what will form the midpiece. The mitochondria will supply energy for sperm movement. Release of mature spermatids into the tubular lumen (spermiation) is accompanied by the loss of the spermatid cytoplasm. The residual cytoplasm is endocytosed and forms residual bodies within the Sertoli cell. The final spermatozoa are ideally designed to transport DNA from the male to the oocyte, with little cytoplasmic baggage, a good mitochondrial engine, and a large tail for propulsion.

Immature germ cells develop in the basal area around the circumference of the seminiferous tubule. As spermatogenesis progresses, developing sperm advance toward the central lumen (Figure 3). The Sertoli cell, the ‘nurse cell’ of the testis, supports, nourishes, and protects the developing germ cells that it surrounds. Sertoli cell tight junctions form a ‘blood-tubule’ barrier that prevents the entry of blood-borne materials and maintains a specific tubular milieu necessary for germ cell development. In the rat, it takes ∼56 days for spermatogonia to complete spermatogenesis and be released from the testis. Spermatogonial differentiation is initiated every ∼12.9 days within the seminiferous tubules. At any given time there will be germ cells from successive generations and at different phases of development within the seminiferous tubules. Fourteen stages of spermatogenesis have been defined based on nuclear morphology and the appearance of the acrosome in the spermatid. The seminiferous epithelium cycles through the stages of spermatogenesis in a time-dependent manner. Different stages follow one another along the length of the seminiferous tubule in what is known as the ‘wave of spermatogenesis’. This progression is necessary to maintain continuous sperm production. If there were no ‘wave’, spermatogonia throughout the testis would enter spermatogenesis at the same time and fertility would become episodic.

Figure 3. Diagrammatic representation of a portion of a seminiferous tubule. L, Leydig cell; M, myoepithelial peritubular cell; SC, Sertoli cell; Sg, spermatogonium; Sp, spermatocyte; Sd, spermatid. (Reproduced from Lamb JC, IV and Foster PMD (1988) Physiology and Toxicology of Male Reproduction. San Diego: Academic Press, with permission from Elsevier.)

The stages of spermatogenesis differ between species. Therefore, the duration and cycle length of spermatogenesis also differs between species. In the human, it is thought that there are six stages of spermatogenesis defined by specific cellular associations. This is in comparison to 14 stages in the rat. Interestingly, the human male may have no clearly defined ‘wave’ of spermatogenesis arranged consecutively along the length of the seminiferous tubule. While some researchers believe that human germ cell development occurs along helical and longitudinal axes, others believe that the arrangement of stages of spermatogenesis may simply be a random occurrence. From a toxicological point of view, germ cells at different stages of development and differentiation may have different susceptibility to toxicants.

The Excurrent Ducts and Sperm Maturation

Spermatozoa leave the testis by first passing through the rete testis, then flowing through the efferent ductules to the epididymis. These reproductive structures are collectively known as the excurrent ducts (Figure 4). In the rodent, the efferent ductules connect to the initial segment of epididymis. In humans, however, the efferent ductules are embedded within the head (caput) of the epididymis. Efferent ductules are comprised of epithelial cells that surround an open lumen. The ductule epithelial cells are specialized for reabsorption, with the portion adjacent to the testis absorbing the majority of fluid and the portion adjacent to the epididymis absorbing small proteins and other macromolecules released with sperm. From the efferent ductule, the concentrated sperm enter the epididymis.

Figure 4. Structural relationships between the testis and the epididymis. (Reproduced from Zaneveld LJD and Chatterton RT (eds.) (1982) Biochemistry of Mammalian Reproduction. © New York: Wiley. This material is used by permission of John Wiley & Sons, Inc.)

The mammalian epididymis is a highly coiled duct where sperm undergo maturation and are stored prior to ejaculation. The epididymis is comprised of a head (caput), a body (corpus), and a tail (cauda), which can be defined by their relative location, tissue characteristics, and cell types. Within a connective tissue sheath, the epididymis is a complex of tubules lined with columnar epithelial cells attached to a basement membrane. Epithelial cell height decreases and luminal diameter increases from the initial segment to the cauda of the epididymis. There are several distinct epithelial cell types found in the mammalian epididymis, including the principal, narrow, basal, clear, and halo cells. The principal cells represent between 65% and 80% of the entire epithelial cell population and are involved in absorptive and secretory processes.

Sperm entering the epididymis from the testis are functionally immature and require further differentiation within the epididymis to become motile and to gain the ability to fertilize oocytes in the female reproductive tract. Sperm maturation events have not been completely elucidated. However, research indicates that sperm maturation is a complex process that involves the remodeling of the sperm plasma membrane within a changing luminal environment. The composition of the epididymal milieu is controlled in part by the epididymis–blood barrier and the active uptake and release of specific macromolecules. As sperm transit the epididymis, they are exposed to different epididymal ‘microenvironments’ that are important for sperm maturation. As sperm mature, they are distinguished by the loss of the cytoplasmic droplet, acrosomal and nuclear changes, and alterations to lipid and protein composition, all of which may be important to sperm gaining their fertilizing ability.

When mature spermatozoa reach the cauda of the epididymis they are stored until ejaculatory release via the vas deferens. Spermatozoa are discharged through the ejaculatory duct. The major portion of ejaculate volume is made up of products secreted by the accessory sex glands: the seminal vesicles, the prostate, and the bulbourethral glands. Rodents also have coagulating glands and preputial glands. Using mature spermatozoa from the cauda epididymis, it has been demonstrated that the secretions of the rodent accessory glands are not important for successful in vitro fertilization. However, there is a reduction in in vivo fertility when accessory gland products are not present in semen, indicating the importance of these components to successful reproduction.

Recently, it has been demonstrated that an immature human spermatid can be injected directly into an oocyte, resulting in successful pregnancy and birth. In practice, the success rates of intracytoplasmic sperm injection (ICSI) vary from 0% to 68%, depending on the number of oocytes injected, the age of the mother, and the quality of sperm. Currently there are no standardized indications for the use of ICSI for infertile couples. However, there is general agreement that ICSI should be used when male infertility (as diagnosed by semen analysis) is a factor. Some severe cases of male infertility are associated with chromosomal aberrations (e.g., aneuploidies, deletions). Therefore, the use of ICSI has raised concerns about the risk of transmission of chromosomal or genetic defects to embryos and negative consequences during development. Recent data have also suggested that the technique of ICSI, which bypasses the normal barriers of fertilization, may itself be responsible for alterations in the viability and health of fertilized embryos. Notwithstanding these concerns, the health of a majority of children delivered after ICSI has been normal.

Hypothalamic–Pituitary–Gonadal Axis

Neuroendocrine control of gonadal function is regulated through the hypothalamus in the brain and the closely associated anterior pituitary gland (Figure 5). Gonadotropin releasing hormone (GnRH) is released from the hypothalamus in a pulsatile manner, and carried in the blood supply directly to the anterior pituitary. After being stimulated by GnRH, the pituitary releases the gonadotrophins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH circulate in the blood and reach the testis where they play a central role in regulation of testicular function. Like GnRH, LH and FSH release are most likely pulsatile in nature. In the testis, LH targets the Leydig cells, where it binds to receptors and stimulates steroidogenesis. Testosterone production is episodic, coincident with the pulsatile release of LH. The Sertoli cell is the testicular target for FSH. The complete role of FSH in spermatogenesis is as yet unknown. However, FSH is necessary for spermatogenesis presumably due to its involvement in Sertoli cell function.

Figure 5. Neuroendocrine control of the male reproductive system. (Reproduced from Heindel JJ and Treinen KA (1989) Physiology of the male reproductive system: Endocrine, paracrine, and autocrine regulation. Toxicology Pathology 17 (2): 411–445, with permission from Society of Toxicologic Pathology.)

Hormonal regulation is through a series of feedback mechanisms taking place at both central and peripheral sites. To complete the endocrine feedback loops, testosterone regulates LH production, while inhibin and other Sertoli cell products regulate FSH secretion. These feedback loops modulate the release of GnRH from the hypothalamus as well as LH and FSH from the anterior pituitary. Within these loops, factors that perturb one component may alter regulatory influences on another. For example, if the Leydig cells were damaged, there could be a decrease in testosterone production. In response to low circulating levels of testosterone, LH release would increase in an attempt to restore testosterone production.

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Reproductive System, Female

Bill L. Lasley, in Encyclopedia of Toxicology (Second Edition), 2005

Germ Cells

Unlike the testes, in which steroid production can proceed in the absence of spermatogenesis, the ovary can function as an endocrine organ only if viable germ cells are in residence. Toxicants that eliminate the resting germ cells automatically eliminate all endocrine function. Since all aspects of female reproduction are dependent on ovarian steroids, the growth, development, and integrity of the entire reproductive system will be disrupted by loss of the germ cells. A complete loss of ovarian function would ensue and, in humans, menstrual function would cease as it would with complete hypothalamic; pituitary dysfunction. In contrast, toxicants that adversely affect only the oocytes which have ended their resting phase and begun to mature will interrupt only the current ovarian cycles as additional oocytes can be recruited from the resting germs cells. Such compounds may be ‘silent’ hazards having the effect of delaying conception only slightly. Exposure to such toxicants would most likely be recognized through menstrual dysfunction, long menstrual cycles, and possibly as a delay to conception.

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Reproductive and Endocrine Toxicology

L. Johnson, ... C.E. Johnston, in Comprehensive Toxicology, 2010

11.02.3.7.5 Aging

Aging affects the testis and other reproductive tract organs. Benign prostatic hyperplasia is a common clinical finding in aging humans and aged dogs with potentially detrimental effects on life. Impotence increases with aging and limits the natural deposition of semen in the female reproductive tract. Not only is there a reduction in the number of sperm cells, but there are also changes in motility of sperm cells and increases in abnormal forms (Blackman 1990).

As measured by a decline in serum testosterone concentrations, endocrine function of the testis declines with age. There are varying reports on the effects of age on Leydig cell number (de Kretser and Kerr 1994). In the human there are reports of decreased, increased, and no difference in older men compared to young men. However, most data support an age-related decline in Leydig cell number with or without an effect on spermatogenesis (Kaler and Neaves 1978; Neaves and Johnson 1985; Neaves et al. 1984, 1985). There is no age-associated attrition in Leydig cell number in the rat (Kaler and Neaves 1981), and the stallion demonstrates an increase in Leydig cell number with age up to 20 years of age (Johnson and Neaves 1981). A decrease in sexual activity is associated with the decline in serum testosterone concentration (Austin and Short 1982).

With aging, there is a reduction in the number of germ cells and daily sperm production in humans and animals (Johnson 1986b). There is also reduced fertilizing ability of the spermatozoa produced by the aged male (Bishop 1970). A decline in the number of Sertoli cells per testis is found in aged humans and rats (Johnson 1986b; Wang et al. 1993). Additional changes seen in the seminiferous tubules associated with advanced age are increased thickness of the surrounding boundary tissue due to a reduction in the total length of the seminiferous tubule (de Kretser et al. 1975; Johnson 1986b, 1995; Salomon and Hedinger 1982). The increased thickening of the boundary tissue may cause a reduced flow of nutrients or hormone signal to and from the seminiferous epithelium (Johnson 1986b).

The cause of the age-related decline in reproductive potential is complex and may vary among species. Possible etiologies for age-related decline in spermatogenesis include the following: vascular degeneration (Sasano and Ichijo 1969), autoimmune orchitis (Harman 1978), altered Leydig cell sensitivity to LH (Jansz and Pomerantz 1986), deterioration of Sertoli cell function (Baker and Hudson 1983; Johnson 1986b; Johnson et al. 1984d), and hypothalamic–pituitary axis dysfunction (Vermeulen 1991; Vermeulen and Kaufman 1995). The need for information on the effects of aging on the reproductive organs of humans is becoming increasingly critical as couples wait till later in life to have children. As the effects of male reproductive toxicants interact with the aging process, the complexity of male reproductive aging increases.

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