PRINCIPLES OF TOXICOLOGY

214 REPRODUCTIVE TOXICOLOGY
spermatogenic potential after the toxicant was removed. This fits the observed effects on occupationally
exposed humans.
Spermatocytes, particularly at the pachytene stages, are susceptible to damage from ethylene glycol
monoethyl ether (EGME), one of the glycol ethers with considerable potential for human exposure. A
metabolite of EGME, 2-methoxyacetic acid (MAA), may cause indirect damage to the spermatocyte
by decreasing lactate production in the Sertoli cells. Lactate is a key metabolic substrate for developing
spermatocytes.
Spermatids may be a particular target for ethylene dibromide (EDB) toxicity. This is another
compound, used as a fumigant, for which there is a least some information that occupational exposures
may have adverse effects on male reproduction. Effects on the later, spermatid, stages of spermatogenesis
would be consistent with the abnormalities and deficits observed in some occupationally
exposed workers. Experimentally, however, EDB turns out to be an example where the stage specificity
breaks down as the dose increases.
Spermatozoa can be affected by various toxic mechanisms. Epichlorohydrin (widely used intermediate
in plastics/rubbers) is an example of a compound that appears to affect sperm motility by
interfering with metabolism. Motility is required for fertilization and the needed energy is produced
through specialized metabolic pathways that operate within the sperm. Chlorpromazine, a drug used
to treat psychosis, appears to cause metabolic effects on sperm secondary to permeabilizing their
membranes. Agents such as mercury and lead may have a combined effect on both sperm cell
membrane dynamics and on the epididymis. Sperm complete their maturation in the epididymis, and
the secretory and absorptive functions of the epididymal epithelium are required for the maintenance
of viable sperm.
Another important mechanism of toxicity may also be pertinent to mature sperm. Many biochemical
reactions result in the formation of highly reactive radical groups. Cellular phospholipids, important
to the structure of cell membranes, are particularly sensitive targets for reactions with these radicals.
The resulting damage, called lipid peroxidation, can impair the integrity of cell membranes. Free
radicals can be generated during the oxidative metabolism of many different compounds. Some of
those that may be male reproductive toxicants are adriamycin, ethylene dibromide, and the herbicides
paraquat and diquat.
Free radical-induced lipid peroxidation may be important to sperm for two reasons: 1) the
detoxification pathways that typically keep free radicals in check are modified in reproductive tissues
and appear to be especially limited in the sperm cells, and 2) sperm contain highly specialized
membranes that can be easily compromised. Investigations of lipid peroxidation in sperm have only
begun recently, and currently, the only clear occurrence of such damage in human sperm is found in
frozen semen samples. Freezing seems to destroy one of the major anti-oxidant defense enzymes
making the sperm especially susceptible. As further investigations of chemical-induced lipid peroxidation
are carried out, some of the membrane disruption associated with spermatotoxicity may be
better explained.
Sertoli Cells Sertoli cells are in direct contact with the germ cells and provide support for them, both
structurally and functionally (Figure 11.1). By virtue of specialized junctions between Sertoli cells,
which isolate the germ cells from any other somatic cells outside of the seminiferous tubule, the Sertoli
cells create a barrier that provides a degree of insulation and protection from chemicals distributed
through the circulatory system. Thus, when Sertoli cells are targeted by toxicants, not only is their
support of germ cell production impaired, the blood/testis barrier may be disrupted, exposing the germ
cells to more potential damage.
Due to their close relationship with the germ cells, it is not surprising that toxicants which
specifically affect Sertoli cells have a subsequent effect on germ cell production. Some of the
characteristics of Sertoli cell damage are that all stages of developing germ cells are impacted and the
damage is frequently irreversible. This is due to the limited replacement of Sertoli cells; they divide
relatively little in mature males. Also, part of the function of Sertoli cells is to initiate the sequence of