Page 336 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Reproductive Toxicity and Endocrine Disruption Chapter | 17 303

VetBooks.ir gossypol supplied as cottonseed meal or whole cottonseed as well as androgen-induced gene expression (Gray et al.,
2006; Zhang, 2008: Evans, 2017). The AhR-mediated
should not exceed 150 and 600 ppm, respectively, in
effects of TCDD can interfere with the biosynthesis of
young developing bulls, or, similarly, 200 and 900 ppm in
sexually mature animals (Morgan, 2004). testosterone and disrupt testosterone signal transduction
pathways (Jana et al., 1999; Sikka et al., 2005).
Xenoestrogens and Antiestrogens
Phthalates
Reproductive function in sexually mature males can
potentially be adversely affected by exposures to nuclear It is recognized that phthalates, which are used as plastici-
ER agonists or antagonists, as well as by estrogenic or zers and which are abundant within the environment, share
antiestrogenic EDCs acting independently of receptor- a unique antiandrogenic mechanism, which can result in
reproductive dysgenesis in male offspring. Unlike vinclo-
mediated interactions (Evans, 2017). However, it is clear
zolin, phthalates are not androgen receptor antagonists, but
from the feminizing effects of prenatal exposures to DES
(McLachlan, 2001; Newbold et al., 2006) and observations it is also clear that they are not uterotropic nor are they
of androgynization in wildlife species (Edwards et al., capable of inducing a persistent estrus, as would be
2006) that the male fetus is much more sensitive to the expected with estrogenic EDCs (Gray et al., 2006).
adverse effects of endocrine disruptors than male animals Phthalates actually alter fetal Leydig cell function, result-
during the postnatal period (Hess and Iguchi, 2002). It is ing in decreased testosterone synthesis and down-regulated
also important to remember that, even in males, xenobio- expression of insulin-like peptide-3, which is required for
tics which interfere with estrogenic signaling pathways gubernacular cords formation (Foster, 2006; Gray et al.,
can adversely affect normal reproductive development and 2006; Foster and Gray, 2008). Appropriately timed fetal
function (O’Donnell et al., 2001; Hess, 2003). exposure to di (n-butyl) phthalate can result in an abnor-
mal aggregation of Leydig cells in the fetal rat testis,
resulting in a failure of Sertoli cell proliferation and func-
Xenoandrogens and Antiandrogens
tional maturation, similar to what has been proposed as a
Normal phenotypic sexual differentiation of the male possible mechanism the development of TDS in humans
fetus, as well as all of the postnatal events which result in (Sharpe et al., 2003; Mahood et al., 2005, 2006).
the delivery of fertile spermatozoa to the female repro-
ductive tract, is dependent on appropriately timed andro- Toxicants Affecting the Female
genic stimulation of the male. It has been well recognized
for quite some time that xenoandrogens (e.g., anabolic Reproductive Function
steroids and exogenous testosterone and DHT) can
There have been many documented reports of female
interfere with hypothalamic pituitary gonadal feedback reproductive abnormalities associated with exposures of
mechanisms (Figure 17.2), resulting in decreased LH domestic animal species to naturally occurring EDCs
release, sperm abnormalities and testicular atrophy (i.e., phytoestrogens and zearalenone) (Evans, 2011a).
(Ellington and Wilker, 2006). In recent years, there has
Likewise, the adverse endocrine disruptive effects of the
been increasing interest in xenobiotics which can interfere
ergot alkaloids produced by the tall fescue endophyte
with interactions between androgens and their receptors
Neotyphodium coenophialum are also very well under-
or, in some other way, disrupt androgen-dependent signal-
stood (Evans et al., 2004; see Chapter 72 in this book).
ing pathways. The dicarboximide fungicides vinclozolin
Unfortunately, however, there are still instances of
and procymidone and/or their metabolites inhibit the bind-
toxicant-induced subfertility which very likely go unrec-
ing of androgens to nuclear androgen receptors and can
ognized. An effort will be made to review some of the
demasculinize and feminize the prenatally exposed male
major mechanisms of action for toxic insult to the female
fetus or induce important alterations in pre- or peri-
reproductive tract in domestic animals, in the hope that
pubertally exposed offspring (Monosson et al., 1999;
the reader might better understand the potential scope of
Gray et al., 2006). Vinclozolin has also recently been
xenobiotic-induced reproductive effects.
shown to be capable, in some experimental settings, of
inducing epigenetic modifications which facilitate the Selected Female Reproductive Toxicants
occurrence of transgenerational or vertically transmitted and Mechanisms of Action
reproductive abnormalities (Anway et al., 2005; Anway
and Skinner, 2006). Other potential EDCs, including Cell-Specific Reproductive Toxicants
0
linuron, p,p -DDE (another metabolite of DDT), prochlor- In general, the effects of toxicants on specific cell types
az and, more recently, pyrethroid insecticides can also within the female reproductive tract, and especially the
function as androgen receptor antagonists, with PBDEs ovaries, are not as well understood as they are in the testes
acting as competitive inhibitors of the androgen receptor (Thomas and Thomas, 2001). Many female reproductive