Leydig cells reside in the interstitium of the testis and make testosterone and insulin-like 3 for reproductive health. Leydig cells contain a series of androgen biosynthetic and metabolizing enzymes. The luteinizing hormone/cAMP/PKA signaling is critical for the stimulation of steroidogenesis. Environmental toxicants on the Leydig cell function act via disrupting its development, blocking LH/cAMP/PKA signaling, downregulating the expressions of steroidogenesis-related proteins and insulin-like 3 or directly inhibiting one or more enzyme activities for testosterone biosynthesis and metabolic activation. These environmental toxicants include industrial materials and natural resources. This chapter reviews these environmental toxicants targeting Leydig cells.
The mammalian testis is a remarkable immunoprivileged site that protects male germ cells from detrimental immune responses. However, a large spectrum of microbial pathogens, including viruses, bacteria, and parasites, may infect the testis. To overcome its immunoprivileged status and enable local defense against microbial infection, the testis has established its own innate immune system. In addition to having immune cells residing in the interstitial spaces, the testis has tissue-specific cells well equipped with innate immune machinery. The testicular immune environment must be tightly regulated to maintain a homeostasis and disruption of testicular immune homeostasis may impair spermatogenesis and male fertility. Understanding the mechanisms underlying testicular immunoregulation aids the development of strategies for the prevention and treatment of immunological impairment of spermatogenesis. Recent studies have revealed that Tyro3, Axl, and Mer (TAM) receptor tyrosine kinases and pattern recognition receptors (PRRs) play important roles in the maintenance of the testicular immunoprivileged status and local innate immune responses against microbial infections. This chapter focuses on the mechanisms by which TAM receptors and PRRs regulate testicular immune homeostasis.
Meiosis is unique to germ cells in sexually reproducing organisms. Major advances have been made in understanding of meiosis. While sharing common factors with mitosis, meiosis is regulated by the evolution of a large number of meiosis-specific proteins. Genetic studies in model organisms including mouse have elucidated the function and mechanism of meiosis-specific proteins. Although conventional cell biological imaging is an informative tool in illuminating the dynamic chromosome changes during meiosis, the application of superresolution imaging technology provides new structural insights into meiosis. The next-generation sequencing technology such as exome sequencing has begun to identify causative mutations in meiosis-specific genes for human infertility. In vitro meiosis has witnessed significant progress. Here we intend to provide an overview of mammalian meiosis with a focus on recent advances.
The testis is an immunologically privileged site with a unique immunosuppressor microenvironment able to tolerate haploid germ cell antigens that appear at puberty and to easily accept tissue grafts. However, this immunosuppressed microenvironment does not prevent the testis from developing inflammatory and immune reactions in response to different stressors such as pathogens or tissue damage. Under inflammatory conditions spermatocytes and spermatids are the main target of immunological attack; these cells die by apoptosis through external and mitochondrial pathways, whereas basal germ cells are protected from death by overexpressing Bcl-260. Diagnosis of human autoimmune orchitis associated with subfertility or infertility, a chronic inflammatory pathology, is possible only by histopathological evaluation of testis biopsy, an invasive procedure. In pathologies like orchitis and spermatogenic arrest, regeneration of spermatogenesis seems to be possible since spermatogonia remain within the seminiferous tubules despite the loss of postmeiotic germ cells.
The Golgi apparatus of germ cells of the testis of adult rats was isolated and subjected to a proteomics analysis with 1318 proteins characterized and 20 localized in situ by light microscope immunocytochemistry. The data revealed unexpected temporal distributions of the 20 germ cell Golgi localized proteins from chaperones to protein-folding enzymes involved in protein maturation. Some proteins were selective for the Golgi apparatus of germ cells spanning the greater part of germ cell differentiation (spermatogenesis). Others were selective for spermatocytes and/or spermatids during acrosome formation. A segregation of two classes of Golgi proteins was also noted during acrosome formation, with some localizing to both the Golgi and acrosome, while others were restricted solely to the Golgi apparatus. Several Golgi markers defined the postacrosome Golgi migration. In addition, some proteins were expressed selectively during the last step of germ cell differentiation (i.e., step 19 spermatids) at a time when the Hermes body (cytoplasmic droplet) was being formed. In the case of the isolated Hermes body of epididymal sperm, 30 non-Golgi proteins were chosen from 1511 characterized by proteomics. These proteins were mapped according to the 14 stages of the cycle of the seminiferous epithelium, with a correlation being noted with specific germ cell organelles that may lead to an understanding of the functional significance of these proteins. In addition, the expression profile of the 30 non-Golgi proteins was compared to that of the 20 Golgi localized proteins according to the 14 stages of the cycle. In this way, similarities in waves of expression of these two different classes of proteins could be compared to reveal functional implications.
Studies of endocrine disrupting chemicals (EDCs) have raised concerns that environmental toxicants possibly impact reproductive health by disrupting programming of endocrine signaling pathways during development. Indeed, indications of a global decline in sperm production capacity in the adult population as well as a higher incidence of newborn urogenital anomalies, testicular cancer, and obesity in the population have been associated with the marked increase in use of industrial chemicals in the last few decades. Chemical exposures occurring in the fetal period are linked to altered sexual differentiation, and consequently, postnatal reproductive development. Diverse cell types expressing FSH, LH, steroid hormone receptors, growth factors, and other cytokines that act as autocrine or paracrine regulators populate the testis. Given the complexity of cell associations in the seminiferous epithelium, disruption of individual testicular cells by chemical toxicants has the potential to alter the pattern of cell-cell interactions necessary to optimize testicular function. This chapter identifies a number of toxicant effects in testicular cells and discusses the potential for disruption of testicular cell-cell interactions. Further studies are warranted to delineate chemical-induced changes in transcriptional regulation of germ cell development in order to generate mechanistic data to support risk assessment of the population.
Spermatogenesis is highly dynamic and precisely controlled in space and time and is accompanied by extraordinary changes in each cell's cytoskeleton. This chapter provides an overview of the actin cytoskeleton in spermatogenesis, highlighting the role of actin dynamics in particular processes in the seminiferous epithelium. After the last meiotic division, haploid spermatids enter spermiogenesis as small, round, very transcriptionally active cells, yet they finish the process as long, transcriptionally inert spermatozoa with dense, characteristically shaped nuclei and long flagella capable of motility. Filamentous-actin tends to be concentrated at intercellular junctions between adjacent Sertoli cells where they contribute to the blood-testis barrier, and at junctions between Sertoli cells and elongating spermatids prior to their release from the epithelium at spermiation. The Sertoli cell ectoplasmic specialization consists of a layer of hexagonally packed actin filaments recognizable by electron microscopy located between the plasma membrane and a cistern of endoplasmic reticulum.
