PRINCIPLES OF TOXICOLOGY

germ cell development. Without Sertoli cells, remaining progenitor germ cells are unable to begin the
spermatogenic cycle.
The solvent n-hexane is a demonstrated reproductive toxicant. Its testicular toxicity is related to
interference with microtubule formation in Sertoli cells by the metabolite 2,5-hexanedione. The
susceptibility of Sertoli cells to a microtubule poison is understandable since Sertoli cells form a
scaffolding supporting multiple layers of germ cells and this function relies on the assembly of
microtubules. This process involves extensive remodeling of the Sertoli cell architecture as the germ
cells are moved through the seminiferous tubule, and such remodeling is heavily dependent on
microtubule formation.
Some of the phthalate plasticizers also appear to affect Sertoli cells. The toxicity appears to occur
in the Sertoli cells, involving a breakdown of the attachments between Sertoli cells and germ cells.
Thus, all of the spermatogenic cells in the developmental sequence at the time of intoxication may be
compromised.
Bioactivation of tri-o-cresyl phosphate (TOCP) is required prior to its effects on Sertoli cells.
Interestingly, the metabolism occurs in the Leydig cells but does not appear to interfere with their
function. The reactive metabolite subsequently reaches the Sertoli cells, which are damaged, and
spermatogenesis is subsequently impaired.
Another Sertoli cell toxicant of interest in occupational toxicology is dinitrobenzene (DNB). This
compound, and structurally related analogues, appears to disrupt Sertoli cell function, possibly through
involvement in a metabolic reaction cycle that depletes the cells of important reducing equivalents,
impairing their functional support for the spermatogenic cells. Subsequently, all of the stages of
developing germ cells may be compromised.
The Sertoli cell tight junctions can also be affected by toxic agents, disrupting the blood/testis
barrier. Platinum-based anti-neoplastic drugs, such as cisplatin, appear to operate in this manner. The
germ cells divide improperly subsequent to this toxicity; however, it is not clear whether this is due
directly to exposure through the disrupted barrier or if the Sertoli cells are incapable of directing germ
cell development properly.
Leydig Cells Leydig cells are located outside, but surrounding the seminiferous tubules. Their major
function is producing testosterone, a key to regulating spermatogenesis as well as male reproductive
development and behavior. There are several toxicants that can be demonstrated to affect Leydig cells
experimentally. It is not clear, however, whether any demonstrable human reproductive toxicity is
primarily due to actions on Leydig cells. In part, this is because androgen regulation is so complex that
it is difficult to determine which observations are primary toxic responses and which result secondarily
from hormonal dysregulation. Also, several of the toxicants with specific actions on Leydig cells can
also cause responses in other cell types, depending on the dose received.
A well-described experimental Leydig cell toxicant which does not appear to directly affect other
testicular cell types is ethane-1,2-dimethanesulfonate (EDS). This compound affects androgen production
by the Leydig cells and appears to interfere with specific early steps in the synthesis of steroid
hormones. While the mechanism leading to cell death is not clear, EDS does kill the Leydig cells. The
eventual result of EDS toxicity is, somewhat predictably, impaired spermatogenesis. In addition, Sertoli
cells, which are dependent to some degree on Leydig cell secretions, may also be damaged.
Among the toxicants with significant human exposure that operate primarily on the testis, diethylhexyl
phthalate and its metabolites are the only example with specific Leydig cell effects. In addition
to their Sertoli cell effects, the phthalates also appear capable of interfering with steroid synthesis and
Leydig cell function. It is not yet clear what the relative contribution of the Leydig cell damage is to
the resulting spermatotoxicity.
Hormonal Regulation and the Hypothalamic-Pituitary-Gonadal Axis
11.1 MALE REPRODUCTIVE TOXICOLOGY 215
Disruptions of male reproductive function can also occur secondary to toxic responses in the endocrine
system. Androgen production in the testes is regulated primarily by luteinizing hormone (LH), a