Page 480 - The Toxicology of Fishes

460 The Toxicology of Fishes

atoms (C-21 steroid) by the P450 enzyme cholesterol side-chain cleavage (P450scc). This enzyme is
present on the inner mitochondrial membrane and has been characterized in teleosts (Takahashi et al.,
1993). Pregnenolone, in turn, undergoes a series of isomerizations and hydroxylations by steroidogenic
enzymes—3β-hydroxysteroid dehydrogenase (3β-HSD), 17α-hydroxylase (P450c17), 21-hydroxylase
(P450c21), 11β-hydroxylase (P450c11), and 20β-dehydroxysteroid dehydrogenase (20β-HSD)—to form
the C-21 steroid hormones progestins and glucocorticoids (Nagahama, 2000). 17α-Hydroxyprogesterone
is converted to androgens (C-19 steroids) by P450c17, which has 17,20 lyase activity (removes the side
chain) and by 11β-hydroxysteroid dehydrogenase (11β-HSD) to produce 11-ketotestosterone. Androgens
are subsequently converted to estrogens (C-18 steroids) by the aromatase enzyme (P450arom). The sex
steroids (estrogens, androgens, and progestins) are produced in the theca and granulosa cells in the ovary
and primarily in the Leydig or interstitial cells in the testis. Sex steroids have both endocrine and paracrine
effects mediated by binding to specific receptors on distant target tissues, such as the liver and hypo-
thalamus, and within the gonads themselves. Sex steroids are transported in the blood bound to sex-
steroid-binding proteins (Laidley and Thomas, 1994, 1997). The pattern of steroidogenesis changes
during the reproductive cycle in both males and females, from the production of estrogens and androgens
during the period of gamete production (gametogenesis) to the production of progestins during gamete
maturation and spawning.

Endocrine Control of the Reproductive Cycle
Reproductive activity in most fishes is seasonal, and the seasonality becomes more pronounced in fish
that reproduce at higher latitudes. Both external environmental stimuli and endogenous circannual
rhythms are thought to influence reproductive cycles in teleosts, although evidence of the latter has only
been obtained for a few species. Photoperiod and temperature are the major environmental variables
that influence reproductive cycles. Photoperiod changes initiate the reproductive cycle in most temperate
species, whereas temperature changes often control the completion of the cycle to ensure that larval
production coincides with favorable environmental conditions for their survival (Khan and Thomas,
1999). These environmental variables and other factors such as social cues influence the activity of the
reproductive neuroendocrine system by neurochemical signals and neural pathways that have not been
clearly delineated. In addition, the physiological functions of the two gonadotropins FSH and LH have
not been as distinguishable in some fish species as they have been in mammals, based on the limited
data available at present on teleost FSH physiology. FSH (GTH I) clearly has important roles in salmonids
and several other fishes during early gonadal development and vitellogenesis or spermatogenesis, whereas
LH (GTH II) regulates the final stages of the reproductive cycle including oocyte maturation, ovulation,
and spermiation; however, a distinct physiological role for FSH during early gonadal development has
not been demonstrated to date in many teleost species, and low circulating levels of LH have been
reported in several species during this period.
The initial phases of gametogenesis in females—oogonial proliferation and primary oocyte growth—
do not appear to be controlled by pituitary hormones, whereas FSH has been shown to stimulate
spermatogonial proliferation in male salmonid fishes. Gonadotropins, however, clearly have critical
functions during subsequent stages of gamete growth and maturation in both males and females. During
the secondary oocyte growth phase, the gonadotropins stimulate the synthesis of 17β-estradiol in the
granulosa cells and its precursor, testosterone, in the thecal cells and their subsequent secretion into the
circulation. A major function of 17β-estradiol in females is to regulate the hepatic production of
vitellogenins, the egg yolk precursor proteins. Estrogen also regulates the synthesis of vitelline envelope
(zona radiata) proteins in the livers of many teleost species. Vitellogenins are rapidly incorporated into
the growing oocytes, whose diameters increase dramatically during this prolonged period of oocyte and
ovarian growth. The vitellogenins are cleaved into the major yolk proteins lipovitellin and phosvitin, as
well as a nonlipoidal derived protein, the β -component, whose function is currently unknown (Hiramatsu
1
et al., 2002). The physiological significance of the high circulating levels of testosterone in females
during this period is less clear. Testosterone is a precursor for estradiol synthesis, and there is evidence
that it participates in the feedback control of gonadotropin secretion by aromatization to estradiol. Other
ovarian hormones, such as inhibin and activin, and growth factors, such as insulin-like growth factors