167
altering the testosterone production by Leydig cells may cause androgen deprivation over time in the organ. Another feature of testosterone withdrawal is the appearance in the epididymal lumen of round spermatids that have been sloughed from the
testis. However, germ cell loss from the seminiferous epithelium is also a feature of
Sertoli cell toxicants, which complicates the evaluation. Testosterone deprivation
will also reduce the number of qualitatively normal sperm that enter the epididymis
and cause regression of the epididymal epithelium.
Toxicants with a direct effect on the epididymis will alter its structure and function. Effects on the epididymal epithelium may result in degeneration, necrosis and
exfoliation of principal cells. An increase of epithelial cell height due to exposure to
direct acting epididymal toxicants has also been documented, together with a disappearance in clear cells in the cauda epididymis, particularly the proximal cauda. All
effects are commonly restricted to very specific segments of the epididymis, thus
highlighting the importance of examining the entire length of the epididymis. To
date there are about 20 known toxicants with a direct effect on the epididymis (e.g.,
Cadmium, ethane dimethanesulphonate (EDS), diethylstilbestrol (DES), chloroethylmethasulfonate (CEMS), methyl chloride, epichlorohydrin, etc.) (for a review,
see [51]).
In vitro systems have been developed for evaluating the effect of direct toxicants
on the epididymis. Coculture of epididymal epithelial cells and sperm were developed [55, 56] that maintain all facets of normal sperm maturation during epididymal
transit. This includes the morphological integrity of epithelial cells and cocultured
sperm, but also the protein synthesis and secretion by the epididymal cells and the
further association of these proteins to sperm membranes. These coculture systems
also successfully promote the acquisition of the capacity for progressive motility of
the cocultured sperm. In the early 2000s, a novel rat caput epididymis cell line was
characterized [57]. It opens relevant possibilities to study the epithelial cell-cell and
spermatozoa-epithelial cell interactions that are involved in sperm maturation.
There are only few examples of toxicants with a direct effect on spermatozoa
within the epididymal lumen (e.g., epi-chlorohydrin [58]. It must be noted that these
effects are dose-dependent with direct effects on spermatozoa occurring at low dosages (i.e., sperm velocity and fertility), while higher doses induce pathological
changes in the epididymis.
These in vitro systems, together with recent advances in technologies, prompt
the use of Omics strategies to identify e.g. transcriptome and proteome alteration
signatures following exposure to reproductive toxicants. It should now provide an
in-depth understanding of toxicants effects on the epididymis structure and function.
10.5.3 Key Characteristics of Male Reproductive Toxicants
The International Agency for Research on Cancer (IARC) has introduced the ten
key characteristics of human carcinogens to provide a uniform and objective
approach for identifying and organizing the mechanistic evidence to support cancer
10 An Overview of Male Reproductive Toxicants: Facts and Opinions
altering the testosterone production by Leydig cells may cause androgen deprivation over time in the organ. Another feature of testosterone withdrawal is the appearance in the epididymal lumen of round spermatids that have been sloughed from the
testis. However, germ cell loss from the seminiferous epithelium is also a feature of
Sertoli cell toxicants, which complicates the evaluation. Testosterone deprivation
will also reduce the number of qualitatively normal sperm that enter the epididymis
and cause regression of the epididymal epithelium.
Toxicants with a direct effect on the epididymis will alter its structure and function. Effects on the epididymal epithelium may result in degeneration, necrosis and
exfoliation of principal cells. An increase of epithelial cell height due to exposure to
direct acting epididymal toxicants has also been documented, together with a disappearance in clear cells in the cauda epididymis, particularly the proximal cauda. All
effects are commonly restricted to very specific segments of the epididymis, thus
highlighting the importance of examining the entire length of the epididymis. To
date there are about 20 known toxicants with a direct effect on the epididymis (e.g.,
Cadmium, ethane dimethanesulphonate (EDS), diethylstilbestrol (DES), chloroethylmethasulfonate (CEMS), methyl chloride, epichlorohydrin, etc.) (for a review,
see [51]).
In vitro systems have been developed for evaluating the effect of direct toxicants
on the epididymis. Coculture of epididymal epithelial cells and sperm were developed [55, 56] that maintain all facets of normal sperm maturation during epididymal
transit. This includes the morphological integrity of epithelial cells and cocultured
sperm, but also the protein synthesis and secretion by the epididymal cells and the
further association of these proteins to sperm membranes. These coculture systems
also successfully promote the acquisition of the capacity for progressive motility of
the cocultured sperm. In the early 2000s, a novel rat caput epididymis cell line was
characterized [57]. It opens relevant possibilities to study the epithelial cell-cell and
spermatozoa-epithelial cell interactions that are involved in sperm maturation.
There are only few examples of toxicants with a direct effect on spermatozoa
within the epididymal lumen (e.g., epi-chlorohydrin [58]. It must be noted that these
effects are dose-dependent with direct effects on spermatozoa occurring at low dosages (i.e., sperm velocity and fertility), while higher doses induce pathological
changes in the epididymis.
These in vitro systems, together with recent advances in technologies, prompt
the use of Omics strategies to identify e.g. transcriptome and proteome alteration
signatures following exposure to reproductive toxicants. It should now provide an
in-depth understanding of toxicants effects on the epididymis structure and function.
10.5.3 Key Characteristics of Male Reproductive Toxicants
The International Agency for Research on Cancer (IARC) has introduced the ten
key characteristics of human carcinogens to provide a uniform and objective
approach for identifying and organizing the mechanistic evidence to support cancer
10 An Overview of Male Reproductive Toxicants: Facts and Opinions