Page 337 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

304 SECTION | II Organ Toxicity

VetBooks.ir toxicants do not target particular cell lines per se, but, (Cheeke, 1998; Burrows and Tyrl, 2001; Mostrom and
Evans, 2011; Evans, 2011a). It should also be noted that
rather, disrupt the endocrine milieu of the tubular genitalia
other leguminous plants, such as soybean (Glycine max),
or cause changes in ovarian structures secondary to
alterations in the hypothalamic pituitary gonadal axis which is commonly used as a feed source for agricultural
(Haschek et al., 2010). There are, however, a number of animals, can contain varying amounts of isoflavones.
xenobiotics considered to be “ovotoxic.” Phthalates and Alfalfa (Medicago sativa) contains another class of phy-
TCDD can delay or decrease ovulations (Devine and toestrogenic compounds referred to as coumestans
Hoyer, 2005). Ionizing radiation and some of the same (Cheeke, 1998; Mostrom and Evans, 2011).
chemotherapeutic agents reported to adversely affect The relatively inactive, “parent” glycosides for the
rapidly dividing germ cells within the testes (e.g., cyclo- most clinically relevant isoflavones in clover are formono-
phosphamide, nitrogen mustard and vinblastine) can also netin, biochanin A and genestin, and the total concentra-
adversely affect primordial follicles within the ovary tion of these phytoestrogens can be as high as 2 to 4%
(Thomas and Thomas, 2001; Devine and Hoyer, 2005). (20,000 40,000 ppm) in clover (Burrows and Tyrl, 2001).
Several PAHs (i.e., BaP, 3-methylcholanthrene (3-MC) Primarily within the gastrointestinal tract and, especially,
and DMBA) and 1,3-butadiene appear to target oocytes the rumen, formononetin is converted into an intermediate
in preantral follicles, and DMBA, BaP and 1- and 2-bro- metabolite, daidzein, and, then subsequently into the more
mopropane, as well as 1,2-dibromopropane, can adversely estrogenically active phytoestrogen, equol (Cheeke, 1998;
affect antral follicular development (Devine and Hoyer, Burrows and Tyrl, 2001). Conversely, biochanin A and
2005). Exposure to free gossypol has been associated with genestin are initially converted into genestein and then
increased numbers of degenerating embryos in heifers subsequently into estrogenically inactive phenolic com-
(Casteel, 2007). pounds (i.e., phenolic acid and p-ethylphenol).
Like the testes, the ovaries also have some xenobiotic Coumestrol is the primary phytoestrogen in alfalfa.
biotransformation capabilities (Thomas and Thomas, This compound has significantly greater estrogenic activ-
2001; Haschek et al., 2010). As in other organs, oxidative ity than many of the isoflavones present in other legumes,
damage can adversely affect ovarian structure and func- and this activity generally decreases during the drying pro-
tion. In the case of 1,3-butadiene and 4-vinylcyclohexene, cess involved in hay production (Cheeke, 1998; Burrows
the adverse effects of these toxicants on small and grow- and Tyrl, 2001). Coumestrol is usually only present at
ing follicles are due, in part, to the toxic actions of the very low concentrations (10 to 20 ppm) in the vegetative
epoxidated metabolites of these xenobiotics (Devine and stages of alfalfa growth, but its estrogenic activity can
Hoyer, 2005). vary with plant maturity and from year to year (Burrows
and Tyrl, 2001; Mostrom and Evans, 2011; Evans, 2011a).
Heavy Metals A number of clinical syndromes have been associated
with phytoestrogen exposure in domestic animals.
The ovaries do not appear to be as sensitive to the toxic
Precocious mammary development has been reported in
effects of heavy metals as do the testes, and those
several instances of phytoestrogen exposure and can be
adverse effects which are observed are more subject to
especially evident in dairy breeds of cattle and goats
variation between species than what was observed in the
(Evans, 2011a). “Clover disease” in sheep and, to a lesser
male gonads (Thomas, 1995). Anterior pituitary release
extent, cattle is associated with the consumption of the iso-
of FSH and LH and ovarian steroidogenesis appear to be
flavones in clover, resulting in infertility associated with
inhibited by cadmium in the female (Hoyer, 2006). With
abnormal estrous cycles and structural and functional
respect to lead, the neuroendocrine function of the
changes in the cervix (Cheeke, 1998; Burrows and Tyrl,
hypothalamic pituitary gonadal axis appears to be tar-
2001). Phytoestrogen-induced alterations in ovine
geted by lead in the female, as well as in the male
cervical mucus interfere with the slow, sustained transport
(Thomas, 1995; Hoyer, 2006).
of motile spermatozoa from their cervical reservoirs
(Cheeke, 1998). Genestein can induce structural changes
Phytoestrogens and, possibly, irreversible organizational abnormalities in
Several genera of leguminous plants produce estrogenic the cervix and uterus of exposed gilts (Ford et al., 2006).
compounds collectively referred to as “phytoestrogens,” Coumestan exposure in cattle can be associated with vari-
which can be associated with clinically relevant effects in ous and, sometimes, seemingly conflicting clinical presen-
livestock species and companion animals. Species of clo- tations (e.g., hyperestrogenism, nymphomania, swelling of
ver, including subterranean clover (Trifolium subterra- the external genitalia, estrus suppression, inhibition of
neum), red clover (Trifolium pratense), white clover ovulation and cystic ovarian disease) (Cheeke, 1998;
(Trifolium repens) and alsike clover (Trifolium hybri- Casteel, 2007). It is important to remember, particularly
dum), contain phytoestrogens classified as isoflavones when clinical signs are very different from what was