155
In the male, the testis in which spermatogenesis takes place, is an organ which is
very vulnerable to toxicants but also to radiations. Paradoxically, for decades, that
organ had generally not been studied precisely by toxicologists although the situation has changed over the past ten years with the appearance and concept of endocrine disruptors. Recently, the US Food and Drug Administration has announced the
availability of a final guidance for industry entitled “Testicular Toxicity: Evaluation
During Drug Development”. It addresses nonclinical findings that may raise concerns of a drug-related adverse effect on the testes, clinical monitoring of adverse
testicular effects early in clinical development, and the design and conduct of a
safety clinical trial assessing drug-related testicular toxicity (Center for Drug
Evaluation and Research; FDA-2015-D-2306). Interestingly, environmental toxicologists can rely upon this highly valuable guidance when studying the adverse
effects of environmental toxicants on male reproduction.
The function of the male reproductive system is to produce male gamete – spermatozoa - and transfer them into the female reproductive tract. The testis is a crucial
component in this process, as it produces both spermatozoa, testosterone and other
androgens that support male reproductive physiology. Accessory organs and ducts
contribute to sperm maturation and transport, among which the epididymis.
10.2 The Testicular Function
The testis is one of the most complex organs because of its anatomical and functional organization. It is divided into two compartments: the interstitial tissue and
the seminiferous tubules where spermatogenesis takes place. All of these structures
are wrapped in a fibrous envelope called Tunica albuginea (Fig. 10.1).
The interstitial tissue is a connective tissue that occupies the space between the
seminiferous tubules. It contains resident nerves, blood and lymphatic vessels,
Leydig cells, macrophages, and occasionally other cells (i.e., fibroblasts, lymphocytes and mast cells). The primary function of Leydig cells is to produce male steroid hormones, testosterone and it’s 5α-reduced metabolites. Testosterone helps to
differentiate and develop the male genital glands, as well as the establishment and
maintenance of secondary sexual characteristics. On the other hand, together with
follicle-stimulating hormone (FSH), testosterone has also essential paracrine functions since it ensures the initiation and maintenance of spermatogenesis.
The tightly coiled seminiferous tubules form the bulk of each testis and account
for 60 to 80% of total testis volume in mammals. Seminiferous tubules are bordered
by the peritubular cells and consist of an epithelium formed by Sertoli cells between
which the germinal cells are dividing and differentiate at different stages of spermatogenesis. Peritubular cells co-secrete with Sertoli cells the extracellular matrix
of the Lamina propria and are in contact with them. In rodents, peritubular cells
form intercellular junctions and constitute one of the elements of the so-called
blood-testis barrier (BTB).
10 An Overview of Male Reproductive Toxicants: Facts and Opinions
In the male, the testis in which spermatogenesis takes place, is an organ which is
very vulnerable to toxicants but also to radiations. Paradoxically, for decades, that
organ had generally not been studied precisely by toxicologists although the situation has changed over the past ten years with the appearance and concept of endocrine disruptors. Recently, the US Food and Drug Administration has announced the
availability of a final guidance for industry entitled “Testicular Toxicity: Evaluation
During Drug Development”. It addresses nonclinical findings that may raise concerns of a drug-related adverse effect on the testes, clinical monitoring of adverse
testicular effects early in clinical development, and the design and conduct of a
safety clinical trial assessing drug-related testicular toxicity (Center for Drug
Evaluation and Research; FDA-2015-D-2306). Interestingly, environmental toxicologists can rely upon this highly valuable guidance when studying the adverse
effects of environmental toxicants on male reproduction.
The function of the male reproductive system is to produce male gamete – spermatozoa - and transfer them into the female reproductive tract. The testis is a crucial
component in this process, as it produces both spermatozoa, testosterone and other
androgens that support male reproductive physiology. Accessory organs and ducts
contribute to sperm maturation and transport, among which the epididymis.
10.2 The Testicular Function
The testis is one of the most complex organs because of its anatomical and functional organization. It is divided into two compartments: the interstitial tissue and
the seminiferous tubules where spermatogenesis takes place. All of these structures
are wrapped in a fibrous envelope called Tunica albuginea (Fig. 10.1).
The interstitial tissue is a connective tissue that occupies the space between the
seminiferous tubules. It contains resident nerves, blood and lymphatic vessels,
Leydig cells, macrophages, and occasionally other cells (i.e., fibroblasts, lymphocytes and mast cells). The primary function of Leydig cells is to produce male steroid hormones, testosterone and it’s 5α-reduced metabolites. Testosterone helps to
differentiate and develop the male genital glands, as well as the establishment and
maintenance of secondary sexual characteristics. On the other hand, together with
follicle-stimulating hormone (FSH), testosterone has also essential paracrine functions since it ensures the initiation and maintenance of spermatogenesis.
The tightly coiled seminiferous tubules form the bulk of each testis and account
for 60 to 80% of total testis volume in mammals. Seminiferous tubules are bordered
by the peritubular cells and consist of an epithelium formed by Sertoli cells between
which the germinal cells are dividing and differentiate at different stages of spermatogenesis. Peritubular cells co-secrete with Sertoli cells the extracellular matrix
of the Lamina propria and are in contact with them. In rodents, peritubular cells
form intercellular junctions and constitute one of the elements of the so-called
blood-testis barrier (BTB).
10 An Overview of Male Reproductive Toxicants: Facts and Opinions