PRINCIPLES OF TOXICOLOGY

11.2 FEMALE REPRODUCTIVE TOXICOLOGY 219
reasons that associating these occurrences with a particular exposure is difficult. In addition, pregnancy
failure occurs frequently as well, and can be due to problems with either the female or the developing
embryo.
There are also some fundamental differences in female germ cell production that relate to the
potential mechanisms of toxic injury. In contrast to the constant cellular division required to generate
millions of new sperm each day, the ovary contains all of the eggs that will ever be ovulated, and then
some, by the time of birth. All mitotic divisions and the initial stages of meiosis have been completed
by the middle of fetal development and result in the generation of around 10 million primary oocytes
arrested in the meiotic progression. Subsequently, a rapid process of degeneration (atresia) occurs, and
there are around one million primary oocytes left at birth. Atresia continues somewhat more slowly
throughout life, and the mature woman has around a half a million oocytes with the potential to develop
into mature eggs.
In the human, a handful of the primary oocytes begins the process of folliculogenesis during each
menstrual cycle, but typically only one forms a completely mature follicle and is ovulated. Estimating
the number of menstrual cycles in a typical reproductive lifetime, only around 500 germ cells ever
complete development. There is no further division of the germ cells prior to leaving the ovary and
while there are somatic cells that divide and develop to support the maturing egg, this occurs over the
course of about two weeks. Clearly, female germ cell production does not rely on mass production and
rapidly dividing cell populations. Correspondingly, the overall process is less susceptible to cytotoxic
compounds that operate against dividing cells.
Oocyte Toxicity
This being noted, however, some of the powerful antineoplastic drugs are still capable of disrupting
oocyte development, including cyclophosphamide, chlorambucil, busulfan, and vinblastine. Experimental
results indicate that busulfan may be capable of destroying the arrested, primordial oocytes,
preventing further maturation and ovulation. Other alkylating agents appear to work only on the
follicles developing at the time of exposure. For the reproductive process as a whole, this is
advantageous, since other primordial oocytes are still available for future cycles of folliculogenesis.
While there is experimental evidence that ovarian-derived metabolites of some polycyclic aromatic
hydrocarbons (PAHs–combustion byproducts) are also capable of destroying the primordial oocytes,
there is limited information on ovotoxicity relating to occupational or environmental exposures. There
are no good examples of human reproductive toxicants that appear to affect egg production under such
circumstances. This is surely due in part to difficulties in analyzing ovarian toxicity that have slowed
down the identification of toxicants with the ability to target the ovary. Experimental findings suggest
that lead, mercury, and cadmium are capable of damaging oocytes, but in light of their generalized
toxicity, this is hardly surprising and probably does not occur in the absence of their major toxic effects
on other systems.
Somatic Ovarian and Reproductive Tract Toxicity
There are a few experimental examples of toxic compounds that can have a direct effect on the somatic
ovarian cells or the reproductive tract. For the ovary, such toxicity relates to successful germ cell
production since the ovarian cells differentiate into layers known as the granulosa and theca, both
integral to the development of mature follicles. 4-Vinylcyclohexene, an industrial compound used in
the production of epoxy resins, appears to be capable of producing generalized ovarian atrophy. Similar
atrophy can be produced with the antibiotic nitrofurantoin, which also has some specific toxicity toward
the cells lining the follicles. The granulosa layer in particular can be targeted by metabolites of some
of the phthalates. It is not clear how such toxicity relates to other effects of these compounds.
The female reproductive tract is responsible for transport of the eggs and sperm to the site of
fertilization and subsequent transport of any fertilized embryo to the site of implantation in the uterus.
Fertilization occurs in the uterine tube, also known as the Fallopian tube or oviduct (Figure 11.3). The