Page 497 - The Toxicology of Fishes

The Endocrine System 477

from the blood and transport it to the lumen surface, where it is oxidized by an enzyme (iodoperoxidase
or thyroid peroxidase). This enzyme also catalyzes the oxidation of certain tyrosines in the thyroglobulin
molecule, resulting in the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT) and subse-
quently the oxidative coupling of these iodinated tyrosines to form the thyroid hormones.
Tetraiodothyronine (T ) is produced by coupling DIT with DIT and is the major thyroid hormone
4
product in fish, whereas triiodothyronine (T ), which is made from coupling MIT with DIT, is produced
3
in much smaller amounts. By a process called pinocytosis, the thyrocytes, upon stimulation by TSH,
incorporate vesicles of thyroglobulin into their cytoplasm, where they fuse with lysosomes, and the
thyroglobulin is enzymatically degraded to yield the thyroid hormones. The thyroid hormones are
subsequently released into the circulation and are transported in the blood in most teleost species bound
to carrier proteins (thyroid-binding globulins). The carrier proteins typically have a higher affinity for
T than T and serve as a buffer and reservoir for these hormones. Thyroxine is converted in several
3
4
tissues including the kidney, brain, and liver to the physiologically active hormone T by removal of an
3
iodide from the outer tyrosine ring by the enzyme 5′-monodeiodinase. A related enzyme, 5-monodeio-
dinase, which is present in certain tissues, catalyzes the removal of iodide from the inner tyrosine ring
to produce reverse T , which is physiologically inactive. The two monodeiodinases further deiodinate
3
T and reverse T to form thyronine, a major route of degradation of thyroid hormones prior to excretion;
3
3
thus 5′- and 5- monodeiodinases have critical roles in T homeostasis, as they regulate both the synthesis
3
and degradation of this physiologically active form of the hormone. T is lipid soluble (lipophilic) and
3
readily diffuses into target cells, where it binds to the thyroid receptor (TR), which belongs to the same
superfamily of ligand-activated transcription factors as nuclear steroid receptors. Similarly, T binding
3
to the TR results in dimerization, but, unlike the steroid receptors, thyroid receptors form heterodimers
with retinoid X receptors (RXRs) to form the activated hormone–receptor complex. The TR component
of this complex binds to thyroid hormone response elements on genes, resulting in alterations in their
rates of transcription. There is also evidence for nongenomic actions of thyroid hormones initiated at
the cell surface in several mammalian models (Norman, 2004).
Interference of the HPT Axis
A variety of environmental chemicals, including PCBs, insecticides, water-soluble fractions of oil,
aluminum, lead, and cadmium, have been shown to alter the thyroid system in fishes by causing decreases
in the circulating levels of thyroid hormones and hepatic 5′-monodeiodinase activity (Chaurasia et al.,
1996; Fok et al., 1990; Folmar et al., 1982; Hontela et al., 1996; Leatherland and Sonstegard, 1978;
Sinha et al., 1992), although the sites and mechanisms of chemical interference with thyroid function
remain poorly understood. Declines in monodeiodinase activity have been reported in fishes after in vivo
exposure to metals and insecticides (Chaurasia et al., 1996; Fok et al., 1990), but it is unclear whether
these chemicals are acting directly on the enzyme or indirectly by altering other endocrine systems that
influence monodeiodinase activity (Eales et al., 1999). Deiodinases contain selenium bound to cysteines
and therefore are potentially susceptible to interference by heavy metals that displace selenium from
these sites in proteins such as cadmium, mercury, and copper. Deiodination has been proposed as a
valuable biomarker of interference of the thyroidal system in fish (Eales et al., 1999). Other potential
sites of xenobiotic interference with thyroid function include interference with neurotransmitter control
of neuroendocrine function (Thomas and Khan, 2004) and binding to the thyroid hormone receptor or
plasma transport protein, although direct evidence is lacking (see reviews by Leatherland, 2000; Eales
et al., 1999; Brown et al., 2004).

Summary

The physiological functions of the gonads and interrenal and thyroid glands in fishes, like those of
tetrapods, are under complex neuroendocrine control by hormones synthesized by the hypothalamus and
pituitary. The hormones secreted by the gonads and interrenal and thyroid glands in turn exert negative
feedback effects on neuroendocrine function; however, the thyroid hormone function in fishes is largely