Page 478 - The Toxicology of Fishes

458 The Toxicology of Fishes

complex to regulatory elements on genes, ultimately resulting in alterations in cell function. Some
hormones, including the gonadal sex steroids, also function in a paracrine fashion by acting locally on
surrounding target cells without entering the circulation.
Most of the information reported to date on endocrine toxicity indicates that xenobiotic chemicals
primarily interfere with gonadal, thyroid, and adrenocortical (interrenal) functions in fish and other
vertebrate species. Specific hormones secreted by the hypothalamus and pituitary regulate the activity
of each of these endocrine glands; therefore, chemical interference with the endocrine axes controlling
these three endocrine functions identified in laboratory studies are briefly reviewed in this chapter.
Evidence for endocrine imbalances in fish populations exposed to endocrine-disrupting chemicals in the
environment is covered in Chapters 22, 24, and 25. The current discussion is limited to evidence obtained
in adult animals, although early developmental stages, such as the period of phenotypic sex determination,
gonadal sex differentiation, and onset of puberty, appear to be especially sensitive to endocrine-disrupting
chemicals (Gray and Metcalfe, 1997; Iguchi, 1999; Norrgren et al., 1999; Strussman and Nakamura,
2002). Most of this chapter focuses on the endocrine control of reproduction by the hypothalamic–pituitary–
gonad axis and the sites and mechanisms of chemical disturbance of reproductive endocrine function,
because the majority of the evidence for endocrine disruption in vertebrates has been obtained in this
system. The literature on these topics is very extensive, so a comprehensive review of all the major
contributions to these fields is not attempted here; thus, the emphasis of this review to a certain extent
reflects the author’s own research interests and findings.

Hypothalamic–Pituitary–Gonadal Axis
Hormones and other factors secreted by the hypothalamic–pituitary–gonadal (HPG) axis control the
development of reproductive tissues and the initiation and precise coordination of the complex processes
that occur during the annual reproductive cycle in teleost fish, culminating in the release and fertilization
of mature gametes. The basic features of the HPG axis in fish are similar to those of other vertebrates
and are shown in Figure 10.1. Environmental cues, such as changes in photoperiod, water temperature
and chemistry, and social stimuli, as well as physiological changes such as alterations of nutritional
state, are detected by peripheral and internal sensory systems, and the information is relayed via neural
pathways to the hypothalamus and associated brain regions. The hypothalamus integrates this infor-
mation, resulting in the secretion of various neurotransmitters and neuropeptides that influence the
activities of gonadotropin-releasing hormone (GnRH)-producing neurons in the preoptic area and
medial basal hypothalamus. GnRH is a decapeptide and the primary neurohormone that controls
reproduction. The GnRH neurons directly innervate the gonadotropin-producing cells in the anterior
pituitary (gonadotropes) of teleosts to regulate the synthesis and secretion of gonadotropins. The GnRH
is released from nerve terminals in the vicinity of the gonadotropes and binds to specific receptors on
the plasma membrane, resulting in activation of intracellular signaling pathways that regulate the release
of gonadotropins. Monoamine neurotransmitters such as dopamine and serotonin also act on the
pituitary to modulate the secretion of GnRH and gonadotropins (Figure 10.1). The neuroendocrine and
intracellular second-messenger systems controlling gonadotropin secretion are briefly summarized in
subsequent sections.
It is generally accepted that the seasonal reproductive cycle in teleosts, like that of tetrapods, is under
dual gonadotropin control by follicle-stimulating hormone (FSH) and luteinizing hormone (LH), previ-
ously named GTH I and GTH II, respectively, in teleosts. FSH and LH are glycoprotein hormones with
molecular weights of approximately 28 to 30 KDa, and they are comprised of two subunits, an alpha
subunit that is common to both gonadotropins and thyrotropin (thyroid-stimulating hormone) and a beta
subunit that is hormone specific. The two gonadotropins are produced in different populations of
gonadotropes within the anterior pituitary (adenohypophysis) and show different secretory patterns during
the reproductive cycle in salmonids, the only teleost fishes in which FSH secretion has been investigated
(Gomez et al., 1999; Swanson et al., 2003). LH and FSH bind to specific G-protein-coupled receptors
on the surface of somatic cells in the gonads. In salmon, one of the gonadotropin receptors specifically
interacts with homologous LH (GTH II) and is localized in granulosa cells in preovulatory ovarian