Spermatogenesis, Heat Stress and Male Infertility
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17 Spermatogenesis, heat stress and male infertility JOHN J. PARRISH 17.1 Introduction 167 17.4 Effects of moderate heat stress 169 17.2 Heat stress 168 17.5 Discussion and future directions 170 17.3 Interactions of heat shock proteins and heat 17.6 Conclusion 171 shock factors 169 References 171 HIGHLIGHTS ●● Apoptosis and germ cell death are a normal part of spermatogenesis. ●● Apoptosis of spermatocytes and spermatids increases during heat stress. ●● Heat stress upregulates the heat stress factors (HSFs) HSF1 and HSF2 leading to prosurvival effects in testicular somatic cells and apoptosis in meiotic germ cells. ●● Androgen production decreases and androgen receptor is downregulated in heat stress, impacting the blood-testis barrier (BTB) and support of meiosis. ●● Unifying theories of heat stress now explain discrepancies in mild to severe heat stress in animal models. ●● Both contraceptive research and improvement of sperm production have exploited research in heat stress. 17.1 INTRODUCTION Germ cells go through mitosis as spermatogonia; meio- sis as primary spermatocytes, secondary spermatocytes The production of sperm occurs within the testes of mam- and round spermatids; and then spermiogenesis, which mals. In most mammals, the testis is held in the scrotal consists of a morphological change to form the spermato- sacks outside of the body cavity and thus is maintained zoa (reviewed in [1]). The general sequence is that type 1A 2°C–8°C below body temperature. In some mammals such spermatogonia divide mitotically three times to form 2 A2, as elephants, porpoises and whales, the testis is within the 4 A3 and finally 8 4A spermatogonia, dividing again mitoti- body cavity, and spermatogenesis may occur at higher tem- cally to form 16 intermediate spermatogonia and then 32 B peratures near the core body temperature. Little is known spermatogonia, and finally 64 primary spermatocytes. The about how spermatogenesis is regulated in such abdominal primary spermatocytes must then cross a junctional barrier testes. This review focuses on mammals with external testes. known as the blood-testis barrier (BTB) that is composed of Once puberty is reached, spermatogenesis occurs contin- a tight junction, desmosomes, gap junction and ectoplasmic uously to produce sperm until a gradual decrease occurs in specializations (2). The basal compartment is between the old age. Within the testes are two general spaces: the semi- BTB and the basement membrane, the adluminal compart- niferous tubules, which contain germ cells, and the Sertoli ment is between the BTB and lumen and then the lumen is cells, which are somatic cells. The seminiferous tubules are in the center of the seminiferous tubule. Following mitosis surrounded by a basement membrane and contractile myoid in the basal compartment, meiosis occurs in the adluminal cells. Outside the seminiferous tubule is the interstitial space compartment in which the primary spermatocytes divide containing Leydig cells, blood vessels, lymphatics and nerve to form 128 secondary spermatocytes and then divide again cells. Myoid and Leydig cells are again somatic cells. to form 256 round spermatids. A modification to the round 167 9780367199302_C017.indb 167 21-08-2019 21:37:25 168 Spermatogenesis, heat stress and male infertility spermatids occurs to transform them into spermatozoa scrotal insulation can produce a rise in testicular tempera- with no further divisions in the process of spermiogen- tures close to body temperature and is similar to experimental esis. The spermatozoa are then released into the lumen in cryptorchidism. Scrotal insulation for 48 hours can produce spermiation. As a developing type A spermatogonia goes an immediate effect on testicular histology, abnormal sperm through these divisions producing the various daughter produce 3–5 weeks later, but following the normal length of germ cells, it is associated with a single Sertoli cell that con- spermatogenesis there is complete recovery to pretreatment trols and coordinates the events of spermatogenesis. There levels of germ cell differentiation and production of sperm is also a coordination along the length of seminiferous (1,16,17). A common approach in rodents that has also been tubules consisting of waves and cycles that ensure a steady applied to some livestock species is a short-term increase production of sperm. As a normal part of spermatogenesis, for 30–120 minutes in scrotal temperatures to 41°C–43°C, there is an overproduction of germ cells that if allowed to well above body temperature (12,19,20). This is a more severe continue would disrupt the BTB and function of the semi- procedure with spermatogenesis often completely disrupted, niferous tubule. The processes of apoptosis and autophagy although in some cases, recovery can occur with very short are thus normal events that limit the eventual number of heat exposure (12). Increasing environmental temperatures spermatozoa produced (1,3–5). In porcine spermatogenesis, into the range of 35°C–37°C for several hours a day followed only 10%–30% of the potential spermatozoa are produced by returning animals to normal conditions of 21°C–23°C (1,6,7), while approximately 25% reach this point in rodent can also produce similar changes but requires exposure for and human spermatogenesis (3). most of the length of spermatogenesis and a range from 3 to Stressors are now known to exploit the decretory pro- 6 weeks to achieve consistent results (18,21). Changing envi- cesses of apoptosis and autophagy during spermatogenesis ronmental temperatures were intended to mimic changes (4). Many stressors disrupt thermoregulation of the testis, seen during warmer months of the year, but just measuring such as increased environmental temperatures, cryptor- semen or testicular tissue response to animals under sum- chidism, febrile disease, fever as a result of vaccination or mer conditions produces variable results, as conditions do obesity (4,8,9). In humans, this may also be as a result of not remain constant and may or may not increase in a par- lifestyle choices, but in livestock, it is human intervention ticular year (1). from designs of housing, environmental controls or other Most of our detailed knowledge of heat stress mechanisms management factors. The end result of these heat stressors of damage in the testis comes from rodent models. While is a decrease in the number and quality of sperm produced. both testicular and epididymal germ cells are sensitive to There have been many studies examining the molecular heat stress, we focus on the testicular cells. Germ cells and, mechanisms of spermatogenesis (1–3,10,11). The goal has in particular, primary spermatocytes undergo apoptosis, and been to either understand the mechanisms that might be if they survive will often contain damaged DNA and poor exploited for contraception or how to increase the number fertility when ejaculated as spermatozoa (22–24). This is also and quality of sperm produced. The former has focused on true in the bull (16,17). Both intrinsic and extrinsic pathways research related to rodent, nonhuman primate and even of apoptosis occur in response to heat stress in primary sper- humans. The latter is work principally with livestock spe- matocytes and round spermatids (4), as well as disruption cies such as porcine, bovine, ovine and even equine. The to the BTB, which then also impact survival of primary and work with heat stress is converging on a unified theory of secondary spermatocytes, and spermatids (12). The intrin- how apoptosis and other cell death pathways play a role sic mechanisms of apoptosis involve the mitochondria, heat in normal, pathological and environmental regulation of shock factors and heat shock proteins, while the extrinsic spermatogenesis. effects are from Sertoli cells and involve secretion of Fas ligand (FasL) from Sertoli cells and binding to Fas receptors 17.2 HEAT STRESS on germ cells that then activate the apoptotic process involv- ing caspases (5). Both the extrinsic and intrinsic pathways Studies in a variety of species come to the same conclusion also involve the p53 system that triggers proapoptotic events about heat stress. First there is a decrease in the amount in the mitochondria and translocation to the nuclease and of sperm produced (1,4,10,12,13). This is associated with cell cycle stasis and death by binding and regulating DNA increased apoptosis of primary spermatocytes through expression (5). Heat also results in the disruption of Sertoli round spermatids (14,15). Interestingly, even sperm that sur- cell–Sertoli cell junctional complexes of the BTB that are vive this apoptosis may have damaged DNA and are of lower essential for meiosis to occur in the adluminal space (2,5,12). fertility (16,17). Animal models have used increased envi- While we now know much about the control of sper- ronmental temperatures, mild local scrotal heating, experi- matogenesis by the BTB and Sertoli cells (2) and that heat mental induced cryptorchidism or even short-term higher induces a variety of molecular changes to the testes (4), the temperatures applied to the scrotum (1,18). Human exposure specific sequence of heat stress events remains unclear. Part to testicular heat stress is usually via lifestyle choices, job- of the problem is that there are heat effects on both somatic related conditions or pathological conditions (4). The inten- and germ cells. The impact on Sertoli cells to provide con- sity and/or duration of the heat exposure impact the severity trol and support of the BTB and the Leydig cells to produce of the response to spermatogenesis observed. For example, testosterone that have an effect on Sertoli cells is critical 9780367199302_C017.indb 168 21-08-2019 21:37:25 17.4 Effects of moderate heat stress 169 (12,25,26). Another problem is that different models of In these somatic cells, the set point for activation of HSF1 inducing heat stress are used, for example, 30–120 minutes is 41°C, but in the testis it is activated at 35°C–38°C (34).