Page 310 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Reproductive Toxicity and Endocrine Disruption Chapter | 17 277

VetBooks.ir to “shift,” and a willingness to “step out of the box” and endogenous hormone receptor-mediated activity (Thomas
and Khan, 2005). Xenobiotics which mimic the actions of
discuss endocrine disruption in a broader context will be
endogenous androgens or estrogens (i.e., gonadal steroid
necessary in order to participate in scientific discussions,
to design future experiments and/or to make informed, receptor agonists) are referred to, respectively, as being
medical or policy decisions based on “good” science either “xenoandrogens” or “xenoestrogens.” Conversely,
(McLachlan, 2001; Guillette, 2006). For the purposes of reproductive toxicants which inhibit or block endogenous
this chapter “endocrine disruption” will refer to the estrogens or androgens from interacting with their respec-
effects of any synthetic or naturally occurring xenobiotic tive receptors (i.e., gonadal receptor antagonists) are gen-
which can affect the endocrine system of exposed indivi- erally classified as “antiandrogens” or “antiestrogens.”
duals (i.e., the balance of normal hormonal functions) Progestagens” (“progestogens” or “progestins” in some
and, as a result of exposure, cause physiological altera- literature) is a generic term for endogenous or synthetic
tions (Keith, 1997; Hodgson et al., 2000). Within the compounds which interact with progesterone receptors,
broad scope of this definition, reproduction, including and there is evidence of increasing environmental contam-
prenatal and pre-pubertal development, certainly would ination with these types of EDCs.
be expected to be one of the physiological functions Some xenobiotics can act as receptor agonists or
most profoundly affected by chemicals capable of endo- antagonists, depending on the circumstances or tissues
crine disruption. In fact, it could be argued that the involved. “Selective ER modulators” or “SERMs” refer
majority of reproductive toxicants interfere with endo- to a class of xenobiotics which, although originally
crine function in one way or another. However, adverse classified as antiestrogens, can function as either ER
effects on other, “non-reproductive” endocrine systems agonists or antagonists, depending on the tissue in
can also be associated with exposures to xenobiotics, which estrogen-dependent responses are being discussed
and these “non-reproductive” effects need to be taken (Dutertre and Smith, 2000; Katzenellenbogen and
into consideration as well when describing the endocrine Katzenellenbogen, 2000). SERMs are particularly rele-
disruption associated with exposure to a given chemical vant with respect to observed differences in their binding
(Guillette, 2006). affinities to ERα or ERβ and their development as thera-
peutic agents for different types of estrogen-responsive
Mechanisms of Endocrine Disruption neoplasia.
Endocrine disruption encompasses a wide range of
mechanisms of action which can ultimately result in Endocrine Disruption Independent
adverse effects on animal species. The mechanisms of of Receptor-Mediated Interactions
action involved in endocrine disruption can include
Endocrine disruption which is independent of interac-
effects which are mediated directly by interactions
tions between xenobiotics and endogenous hormone
between the xenobiotic and an endogenous hormone
receptors can occur in a variety of different ways.
receptor (i.e., the xenobiotic functions as a ligand for an
Xenobiotic exposure can result in alterations in the
endogenous receptor and a receptor ligand complex is
number of hormone receptor sites (up- or down-regula-
formed), as well as those adverse effects which alter hor-
tion) or can cause direct or indirect hormone modifica-
monal functions without direct interactions between the
tions which alter hormonal function (Keith, 1997).
toxicant and an endogenous receptor (Keith, 1997). In
Xenobiotics can change the rate of synthesis or destruc-
addition, it should be noted that some xenobiotics are
tion of endogenous hormones and can alter how hor-
capable of causing endocrine disruption by functioning as
mones are stored, how they are released into and/or
an endogenous hormone receptor ligand, as well as by
transported within the circulation or even how they are
mechanisms of action which are independent of the
eventually cleared from the body (Keith, 1997; Sikka
formation of a xenobiotic (ligand) receptor complex.
et al., 2005). Any xenobiotic which is toxic to organs or
tissues producing hormones (e.g., testis and ovary) has
“Classic” Receptor-Mediated Endocrine Disruption the potential to decrease hormone synthesis and thereby
“Classic” endocrine disruption can involve imitation or indirectly cause endocrine disruption (Devine and
mimicry of the interactions between cellular receptors and Hoyer, 2005). It should also be noted that some of these
endogenous hormones (i.e., receptor agonism) and/or a mechanisms of endocrine disruption are not necessarily
blockade or inhibition of the formation of receptor exclusive of one another. A given xenobiotic can poten-
hormone complexes (i.e., receptor antagonism) tially disrupt the normal balance of hormonal function
(McLachlan, 2001). With respect to gonadal steroids, by more than one mechanism which is independent of
both genomic and non-genomic physiological responses direct interactions between the toxicant and an endo-
can be affected by this mimicry or blockade of genous hormone receptor.