Page 332 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Reproductive Toxicity and Endocrine Disruption Chapter | 17 299

VetBooks.ir Toxicants Affecting the Male Reproductive targets of 2,5-hexanedione (Thomas and Thomas, 2001;
Haschek et al., 2010). The fungicide dibromochloropro-
Function
pane (DBCP) appears to affect the Sertoli cell (Thomas
There have been relatively few documented reports
regarding the adverse effects of reproductive toxicants on and Thomas, 2001), but its metabolites epichlorhydrin
and α-chlorhydrin induce capillary permeability and
male fertility in the major animal species of veterinary vascular damage within the epididymis (Haschek et al.,
interest. Realistically the lack of examples is more likely 2010).
a reflection of the limited number of controlled studies There are a number of reproductive toxicants which
performed using non-rodent mammalian species and/or target-specific populations of germ cells. Spermatogonia,
the number of toxicant-associated reproductive abnormali- spermatocytes, round spermatids and elongate spermatids
ties which remain undiagnosed, rather than an accurate are specifically targeted by busulfan, 2-methoxyethanol,
indication of the scope of the problem (Schrader, 2002). ethylmethane sulfonate and dibromacetic acid, respec-
A large number of chemicals are currently thought to tively (Haschek et al., 2010). Ionizing radiation and a
have the potential for causing abnormalities in male variety of chemotherapeutic agents, including cyclopho-
reproductive function in domestic animals. Based on phamide, nitrogen mustard, vincristine and vinblastine,
extrapolations from effects observed in a various mamma- generally target rapidly dividing mitotic or meiotic germ
lian species and the limited scientific and anecdotal cells in the testes, and TCDD appears to adversely affect
reports, a partial listing of these compounds is presented several populations of spermatozoal precursors (Thomas
in Table 17.1 (Ellington and Wilker, 2006). In the follow- and Thomas, 2001). The compound 7,12-dimethylbenz[a]
ing section a few selected male reproductive toxicants anthracene (DMBA) is toxic to spermatogonia but must
and their proposed mechanisms of action will be undergo a stepwise biotransformation in the Leydig cell
described in order to familiarize the reader with the vari- and, subsequently, the Sertoli cell to produce the ulti-
ous different ways that male fertility can be affected by mately toxic metabolite (Haschek et al., 2010).
reproductive toxicants.

Heavy Metals
Selected Male Reproductive Toxicants
Lead and cadmium are ubiquitous heavy metals and have
and Mechanisms of Action
both been associated with testicular toxicity and impaired
Cell-Specific Reproductive Toxicants fertility in a number of species. Excessive cobalt can
Some reproductive toxicants adversely affect specific potentially interfere with normal spermatogenesis, and
cells within the testes. Ethane dimethane sulfonate is spe- severe cobalt intoxications have actually resulted in gen-
cifically cytotoxic to the Leydig cells, and excessive eralized hypoxia related to increased blood viscosity
exposure to this compound results in complete loss of this which affects the testes (Thomas, 1995). Chromium
population of cells within the interstitium, and, conse- and vanadium have also been associated with adverse
quently, the ability of the testes to synthesize testosterone reproductive effects (Thomas and Thomas, 2001), and
and, in some species, estrogens (Haschek et al., 2010). cis-platinum exposure has been associated with the death
Tri-o-cresyl phosphate (TOCP) is an industrial chemical of spermatocytes and spermatids, as well as disruption of
used in lacquers and varnishes, which inhibits LH- Sertoli cell tight junctions (Thomas, 1995). Although tes-
induced steroidogenesis in the Leydig cells and, after ticular toxicity is generally not observed with excessive
Leydig cell-mediated conversion to its active metabolite, parenteral exposure to zinc (other than possibly secondary
morphological abnormalities in Sertoli cells (Thomas and to hemolytic anemia-related hypoxia) (Thomas, 1995),
Thomas, 2001; Haschek et al., 2010). intratesticular injections with zinc gluconate have been
Sertoli cells are specifically targeted by several toxi- successfully used for chemical castration in several
cants, including diethylhexyl phthalate (DEHP), 1,3- species.
dinitrobenzene (DNB) and 2,5-hexanedione (metabolite Divalent lead is known to interact with physiological
of n-hexane) (Haschek et al., 2010) and the effects of processes involving calcium and generally has an affinity
these xenobiotics are age and species specific (Thomas for sulfhydryl groups. Lead is reported to be directly toxic
and Thomas, 2001). With respect to DNB, the parent to germ cells and Leydig cells and can suppress anterior
compound is converted to its toxic metabolites, nitoso- pituitary secretion of LH and FSH (Thomas and Thomas,
nitrobenzene and nitroaniline, within the target Sertoli 2001). Lead also appears to be able to adversely affect
cells, and, similar to other Sertoli cell-specific toxi- the ability of spermatozoa to fertilize ova, but this effect,
cants, germ cell death and exfoliation occur secondary like others associated with lead exposure, appears to be
to toxic insult to the Sertoli cells (Haschek et al., 2010). dependent on age and individual variations in susceptibil-
Sertoli cell microtubules appear to be the intracellular ity, adaptation and reversibility (Sokol, 2006).