Page 308 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Reproductive Toxicity and Endocrine Disruption Chapter | 17 275

VetBooks.ir within and between a variety of diverse organs. In sexual prolactin inhibitory factor (PIF) and melatonin); peptides
(e.g., oxytocin, adrenocorticotropin hormone (ACTH),
reproduction and mammalian pregnancy, critical commu-
corticotropin releasing factor or hormone (CRF or CRH),
nication even takes place between distinctly different
organisms (i.e., male and female and mother and off- gonadotropin releasing hormone (GnRH) and thyrotropin
spring, respectively). The dependency of reproductive releasing hormone (TRH)); proteins (e.g., activin, inhibin,
function on signaling pathways inclusive of gene tran- insulin-like growth factors, prolactin and relaxin); glyco-
scription makes this physiological process especially proteins (e.g., follicle-stimulating hormone (FSH), lutei-
prone to adverse effects associated with xenobiotic- nizing hormone (LH) and thyroid stimulating hormone
induced disruption of or interference with cell-to-cell, (TSH or thyrotropin)); steroids (e.g., androgens, estrogens
organ-to-organ and/or even animal-to-animal communica- and progestagens); and eicosanoids, which include prosta-
tion. Many of the mechanisms which interfere with physi- glandins (Evans et al., 2007; Evans and Ganjam, 2017).
ological signaling activity can be classified as forms of The actions of hormones on their targets are generally
“endocrine disruption,” which will be discussed in much mediated through receptors which initiate or inhibit some
greater detail in this chapter. sort of signal transduction pathway or are required for
There is a great deal of overlap between the various hormone-induced alterations in gene expression. Hormone
different mechanisms for reproductive toxicity. The level receptor interactions can be modulated by a number of fac-
of exposure to a particular toxicant is an important deter- tors including the amount of hormone present, the affinity
minant of what toxic effects are observed. Xenobiotics of the hormone for the receptor, receptor density and occu-
which “disrupt” endocrine pathways can do so without pancy and interaction with other hormones, receptors and
interactions with endogenous receptors, using mechanisms hormone receptor complexes, as well as a variety of
of action which can cause other forms of toxic insult at endogenous co-activators and inhibitors (Genuth, 2004a;
various dosages. Bigsby et al., 2005). It should be clear by the end of this
chapter that various xenobiotics are also capable, under cer-
tain exposure conditions, of modulating the interactions
Reproductive Toxicants and Teratogens
between endogenous hormones and their receptors.
Any xenobiotic associated with adverse effects on devel-
opment or male or female reproductive function can be
classified as a “reproductive toxicant.” Xenobiotics capa- Gonadal Steroid Hormones
ble of inducing teratogenesis are referred to as “terato- and their “Nuclear” Receptors
gens.” Although any chemicals adversely affecting animal
The primary gonadal steroids (i.e., androgens and estrogens
well-being have the potential to have a negative impact
(some references also include progesterone)) are also
on development and reproductive function, this chapter
referred to as the “sex” steroids, and the imitation and/or
will attempt to focus on mechanisms of actions and toxi-
inhibition of the actions of these hormones by xenobiotics is
cants which specifically target normal embryonic or fetal
what was first referred to as “endocrine disruption”
growth and maturation or have a direct effect upon the
(Krimsky, 2000; McLachlan, 2001). The major androgens
male and/or female reproductive tract. (testosterone and dihydrotestosterone (5α-reductase conver-
sion product of testosterone in the testes and selected non-
Hormones and Hormone Receptors gonadal tissues)), estrogens (estradiol and estrone) and
progesterone and endogenous progestagens facilitate the
The term “hormone” classically refers to a substance development and regulation of reproductive function in ani-
which is secreted into the circulation by a ductless gland mal species, in large part by interacting with (i.e., function-
and which alters the function of its target cells (Hodgson ing as ligands for) receptors which are members of the
et al., 2000). While the traditional “endocrine” aspect of steroid/thyroid (“nuclear”) receptor superfamily, the largest
hormone action involves organ-to-organ signaling (and in family of transcription factors in eukaryotic systems (Tsai
the case of mammalian pregnancy animal-to-animal sig- and O’Malley, 1994; Genuth, 2004a). Receptors in this
naling), it is recognized that hormones can also be superfamily are large oligomeric proteins (Genuth, 2004a),
involved in “paracrine” (cell-to-cell) communication and which generally consist of five domains (A/B, C, D, E and
signaling pathways within the same cell in which they F) (Tsai and O’Malley, 1994). Although specific portions of
were produced (“autocrine” function) (Evans et al., 2007; the gonadal steroid nuclear receptor molecules can interact
Evans and Ganjam, 2017). In vertebrates there are a wide with a variety of co-activators as well as inhibitors, the most
variety of different hormones involved in reproductive important domains of these receptors are generally consid-
function. The major reproductive hormones are generally ered to be those involved in transactivation (N-terminal A/B
grouped according to their basic molecular structure and domain; also C-terminus in estrogen receptors (ERs));
include amino acid derivatives (e.g., dopamine or DNA-binding and hormone receptor complex dimerization