PRINCIPLES OF TOXICOLOGY

212 REPRODUCTIVE TOXICOLOGY
Understanding general mechanisms of action can help categorize chemicals as to the effects that
are possible. It is important to remember that while a mechanism for cellular damage to spermatogenic
cells exists for reactive chemicals in general, not every alkylating agent or reactive metabolite will
actually act as a specific reproductive toxicant. Other factors control the susceptibility of spermatogenic
tissues to particular chemicals. Among the critical factors are the dose level that is received, the extent
of distribution to the target tissue that occurs, and how/where metabolism occurs for the particular
chemical. Individual and species differences in such factors explain the differences in susceptibility
and demonstrate the need to proceed carefully when predicting whether a chemical will be a human
reproductive toxicant.
The energy associated with ionizing radiation, including x-rays, can also result in chemical
modifications to DNA that affect its potential to be copied correctly and to direct cellular functions.
While germ cells at all stages of spermatogenesis can be affected, it appears that some of the early
stages are most susceptible to DNA strand breaks from irradiation. Such breaks can result in
chromosomal malformations in germ cells. In addition, the death of damaged somatic cells (non-germ
cells) can result in the collection of cellular debris in the duct system that carries the germ cells.
In addition to DNA damage that can lead to cell death, there is also the possibility that modifications
of DNA can be repaired incorrectly, producing a mutation. There are cellular mechanisms available to
remove and replace damaged segments of DNA, but there is a certain error rate, albeit low, associated
with this type of repair. When such repair errors occur in a germ cell, there is the possibility that the
resulting mutation could be passed to offspring and become heritable. While this is theoretically
possible and can be demonstrated in some experimental systems, the generation of an inherited human
mutation following chemical-induced DNA damage has not been documented.
Direct and Indirect Modes of Toxicity
Another important toxicological concept well illustrated in the male reproductive system is the
distinction between direct acting toxicants and indirect acting toxicants. Direct acting toxicants may
be reactive chemicals or chemicals with sufficient structural similarity to molecules used in cellular
communication that they can interfere with signaling pathways. Indirect acting toxicants may eventually
cause damage in the same ways, but must first be modified through metabolic reactions or
bioactivated. Ironically, reactive metabolites result frequently from the chemical reactions also used
to break down and eliminate foreign chemicals. The metabolism may take place in the cells or tissues
that are eventually damaged, or may occur in other organs, such as the liver. In the latter case, the toxic
metabolites must be transported to the target tissue.
Some of the best known reproductive toxicants have a direct mode of action on male reproductive
tissues. Lead and cadmium are two examples of metals in this category. Lead can damage genetic
material, disrupting cell division and resulting in cell death. While many different cell types are
susceptible to damage from lead, the importance of continual division during spermatogenesis makes
this process particularly vulnerable.
Cadmium has an interesting direct mode of action on the vasculature surrounding the testis and
epididymis, the adjacent tubular organ in which sperm are stored and mature. Sperm must be kept at
temperatures slightly below core body temperature. Extensive and specialized vascularization is
provided to remove heat from the testis. This vasculature is extremely vulnerable to direct damage by
cadmium. When such damage occurs, the remaining vessels are unable to carry away as much blood,
and thus as much heat. The combination of reduced perfusion with oxygenated blood and higher
temperatures can subsequently destroy the spermatogenic cells.
Many of the alkylating chemotherapeutic drugs have direct modes of action resulting in male
reproductive toxicity, including busulfan and cyclophosphamide. Ethylene oxide, used extensively as
a chemical intermediate in industry and for gas sterilization of medical devices and even foods, also
has direct actions on cellular biomolecules and experimental studies suggest later stage germ cells are
particularly susceptible to its damage. DNA is stabilized by extensive interactions with structural