Page 309 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

276 SECTION | II Organ Toxicity

VetBooks.ir (middle portion containing two helical zinc fingers; In addition, it is also apparent that gonadal steroids can
affect cellular function by non-genomic mechanisms of
C domain); and hormone (ligand) binding (C-terminus;
action involving changes in intracellular concentrations of
E domain) (Genuth, 2004a; Bigsby et al., 2005). While
androgen, estrogen and progesterone receptors, which are ions, cAMP and its second messengers, and the mitogen-
members of the steroid/thyroid superfamily, are often thought activated protein (MAP) kinase pathway. These non-
of as being exclusively nuclear in their location, these recep- genomic mechanisms are independent of the somewhat
tors can also be located in the cytoplasm of some cells (Tsai “time-consuming” alterations in gene expression tradition-
and O’Malley, 1994; Genuth, 2004a). Cytoplasmic and ally associated with gonadal steroids and occur rapidly
nuclear gonadal steroid receptors can be bound to a variety within seconds or minutes (O’Donnell et al., 2001;
of different heat shock proteins, which interact with the Thomas and Khan, 2005). While the rapid, non-genomic
receptor’s hormone-binding domain. Heat shock proteins can effects of gonadal steroids most likely involve receptors
act as “blocking” molecules and are displaced by hormones bound to the plasma membrane, the specific identity and
binding to the receptors (Genuth, 2004a; Bigsby et al., 2005) classification of these receptors remain unclear and might
or as “chaperones” involved in receptor turnover and “traf- involve a number of different receptor types (Razandi
ficking” of these receptors between the nucleus and the cyto- et al., 1999; O’Donnell et al., 2001; Thomas and Khan,
plasm (Pratt and Toft, 1997). 2005; Warner and Gustafsson, 2006).
There is reportedly a single type of androgen receptor
which is a member of the steroid/thyroid superfamily. In Endocrine Disruption
contrast, there are two types of nuclear ERs (ERα and
ERβ), which are the products of distinct genes on separate “Endocrine disruption” is a developing, multidisciplinary
chromosomes (O’Donnell et al., 2001). ERα and ERβ dif- area of research, involving aspects of both toxicology and
fer in their amino acid structure, tissue distribution, affin- endocrinology (McLachlan, 2001). “Endocrine disrup-
ity for selective ER modulators (SERMs) and their role in tion” is also a potential mechanism of action for many
female (Britt and Findlay, 2002) as well as, somewhat toxicants, and this term has been defined in a variety of
surprisingly, male fertility (O’Donnell et al., 2001; Hess, different ways, depending on the circumstances and the
2003). The nuclear progesterone receptor also has two intended audience. Some of these definitions can be fairly
isoforms, progesterone receptor A and progesterone “broad,” such as the one which will be used in this chap-
receptor B (PRA and PRB, respectively), which differ ter (see below). However, “endocrine disruption” can also
slightly in their amino acid sequences and their interac- be defined fairly narrowly with respect to toxicant origin
tions with co-activators. However, unlike ERα and ERβ, (synthetic versus naturally occurring); source or site of
PRA and PRB are the products of a single gene (Brayman toxicant exposure (environmental contamination versus
et al., 2006). occupational exposure); xenobiotic mechanism of action
(receptor agonism and/or antagonism (see definition
below) versus other mechanisms independent of direct
Genomic and Non-Genomic Mechanisms interactions between xenobiotics and receptors); and/or
of Action of Gonadal Steroid Hormones the timing of exposure (pre- natal versus postnatal expo-
Traditionally, the receptor-mediated reproductive effects sures) (Krimsky, 2000, 2001). It is critically important for
of gonadal steroids were thought to occur almost exclu- one to carefully define the context in which “endocrine
sively through interactions between homodimers of the disruption” is being used in order to clearly and accu-
hormone nuclear receptor complexes and specific rately discuss one’s research findings or opinions with
regions of DNA upstream from the basal promoter of a toxicologists, physiologists, wildlife biologists, medical
given gene, referred to as hormone-response elements professionals, regulatory personnel, the popular press
(HREs) or, more specifically, androgen and estrogen- and/or the general public (McLachlan, 2001).
response elements (ARE and ERE, respectively) (Tsai Although the imitation and/or inhibition of the actions
and O’Malley, 1994; Genuth, 2004a). It is now under- of androgens and, especially, estrogens by xenobiotics is
stood that these “genomic” effects of gonadal steroids and what was first referred to as “endocrine disruption,” both
their nuclear receptors, which involve alterations in gene the multidisciplinary area of study and mechanism of
transcription, can, in some instances, involve heterodi- action generally referred to as “endocrine disruption”
mers of different nuclear steroid receptor complexes, have evolved over the years to encompass a wide range
indirect binding of hormone receptor complexes to DNA of specific mechanisms of action which can ultimately
via proteins within a preformed transcriptional complexes result in adverse effects on invertebrate and/ or vertebrate
and even ligand (hormone)-independent “activation” of animals (McLachlan, 2001). As scientists continue to
nuclear gonadal steroid receptor molecules (O’Donnell investigate the effects of xenobiotics on biological sys-
et al., 2001; Bigsby et al., 2005; Thomas and Khan, 2005). tems, the paradigm of endocrine disruption will continue