Page 487 - The Toxicology of Fishes

The Endocrine System 467

with sex pheromone action by binding to their olfactory receptors, resulting in activation of inhibitory
pathways controlling neuroendocrine function and reproductive behaviors (site 1) (Moore and Lower,
2001). Alternatively, the chemicals could act in the hypothalamus to influence neurotransmitter function
controlling GnRH secretion or directly influence GnRH neurons (site 2) (Khan and Thomas, 2001).
Changes in the secretion of GnRH and regulatory neurotransmitters would secondarily affect pituitary
GnRH receptor levels and gonadotropin secretion from the pituitary in response to GnRH. In addition,
certain chemicals can act directly at the pituitary to influence GnRH signaling pathways in the gonado-
trope and gonadotropin secretion (site 3) (Thomas, 1993). These chemically induced changes in gona-
dotropin secretion often result in alterations in gonadal function and development, especially steroid
hormone production and gamete maturation. Some chemicals exert their actions directly on the gonads
to disrupt endocrine function by influencing the activities of gonadotropin second-messenger pathways
and enzymes involved in the synthesis of steroid hormones (site 4) (Ankley et al., 2005; Benninghoff
and Thomas, 2005; Freeman and Idler, 1974; Thomas and Khan, 1997; Van Der Kraak et al., 1992).
Alterations in steroid production can dramatically influence steroid levels in the blood and subsequently
steroid actions at their target tissues such as the gonads, accessory reproductive tissues, liver, and
neuroendocrine system. Increases in the metabolic clearance rate of steroids due to induction of hepatic
cytochrome P450 enzymes by certain chemicals such as polychlorinated biphenyls (PCBs) can also
influence circulating steroid levels (site 5) (Sivarajah et al., 1978; Yano and Matsuyama, 1986). Steroid
hormone action can also be affected at these target tissues by direct interactions of chemicals with both
nuclear and membrane steroid receptors, resulting in agonism or antagonism of steroid hormone action;
for example, the steroid feedback system that influences reproductive neuroendocrine function (site 6)
could be affected by alterations in the production (Kishida et al., 2001), clearance, or action of steroids
(Harris et al., 2001; Khan and Thomas, 1998). Similarly, the stimulation of vitellogenesis by chemicals
could be due to their direct interactions with the estrogen receptor in the liver, which regulates vitellogenin
production (site 5) (Jobling and Sumpter, 1993; Thomas and Khan, 1997); could occur indirectly due
to actions at other levels of the HPG axis that result in alterations in blood estradiol levels; or could be
due to several mechanisms acting simultaneously. For some chemicals, actions at multiple sites via
several mechanisms have been demonstrated (Van Der Kraak et al., 1992).

Mechanisms of Endocrine Toxicity
The main features of the endocrine system, discussed in the previous sections, involves the secretion of
hormones into the circulation, their binding to specific receptors on target tissues, and the subsequent
intracellular hormonal responses. In general, the magnitude of the cellular response to hormones is
dependent on the number of receptors occupied by the hormone which, in turn, is related to the
concentration of free (or loosely bound) hormone in the circulation. Xenobiotic chemicals, therefore,
can potentially influence endocrine function by affecting hormone levels in the blood via alterations in
hormone secretion or metabolic clearance or by interfering with hormone action at the receptor or at
other sites along the hormone signal transduction pathway. Evidence has been obtained for all these
types of endocrine disruption in fishes.

Alterations of Hormone Secretion
Neuroendocrine Secretion
A large body of evidence, mostly circumstantial, indicates that many compounds, including lead, mercury,
organochlorine and organophosphorus pesticides, PCB mixtures, and mimics or antagonists of steroid
hormone action impair reproductive endocrine function (i.e., endocrine-disrupting chemicals [EDCs]
that act on the reproductive system) at the hypothalamic level in mammals, fish, and other vertebrates
(Cooper et al., 1999; Desaulniers et al., 1999; Katti and Sathyaneson, 1986; Khan and Thomas, 1997;
Thomas and Khan, 1997). Investigations of the neuroendocrine targets of EDCs, however, are compli-
cated by the multiplicity and complexity of neuroendocrine pathways that control reproduction and the