br Conclusions br Introduction The terms
Introduction The terms endocrine active and endocrine disruptive have been used to describe an ever-expanding list of naturally-occurring and synthetic compounds that interact with mammalian hormonal systems, and in particular, the reproductive system. These compounds have been associated with adverse reproductive and health effects in wildlife and laboratory animals (e.g. Crain, Guillette, Rooney, & Pickford, 1997, Gray, Wolf, Lambright, Mann, Price, Cooper, & Ostby, 1999). Although the most thoroughly characterized mechanism of action for many of these compounds involves interaction with steroid receptors either as agonists or antagonists, additional mechanisms may be involved. Some other mechanisms that have been proposed are: alterations in steroid receptor levels and/or post-receptor signaling pathways, and changes in metabolism of hormones. These additional mechanisms may be the result of interaction with steroid receptors or with unrelated, compound-specific targets. Hepatic cytochrome P450 (CYP450) chir99021 are a large family of hemoproteins responsible for the oxidative metabolism of a wide variety of xenobiotics (Nebert et al., 1991). In addition, CYP450 enzymes play a role in the degradative metabolism of many endogenous compounds, including steroids (Nebert et al., 1991). An interesting feature of the CYP450 system is that, in rats, these enzymes are expressed in a sex-specific fashion and are responsible for a sexually dimorphic pattern of steroid metabolism. The male specific form, CYP2C11, is virtually undetectable in female rat liver and is responsible for 16α- and 2α-hydroxylation of testosterone (Kamataki, Maeda, Yamazoe, Nagai, & Kato, 1983, Waxman, & Walsh, 1983). In addition, CYP3A2 is expressed at higher levels in males (Gonzalez et al., 1986). The female specific form, CYP2C12, catalyzes the 15α-hydroxylation of steroid sulfates (Kamataki et al., 1983). In addition, steroid 5α-reductase, which is responsible for the formation of dihydrotestosterone (DHT), is expressed at 5-fold higher levels in females than males (Pak, Tsim, & Cheng, 1985, Dannan, Guengerich, & Waxman, 1986). These sex-specific variations in enzyme expression result in distinct testosterone metabolic profiles in male and female rats. The expression of these sex-specific enzymes is developmentally regulated and becomes apparent at puberty. Neonatal gonadectomy and hormone replacement experiments have demonstrated that neonatal androgen “imprints” the male rat for developmental induction of male-specific CYP2C11, for maintenance of male-predominant CYP3A2, and for suppression of female-specific CYP2C12 at puberty (Waxman et al., 1985). Additionally, androgens are important for maintenance of the male pattern of expression at puberty and during adulthood (Pak, Tsim, & Cheng, 1985, Chang, & Bellward, 1996). The expression of steroid 5α-reductase is also regulated at neonatal and pubertal stages of development (Pak, Tsim, & Cheng, 1985, Dannan, Guengerich, & Waxman, 1986, Chang, & Bellward, 1996). Studies on the neonatal imprinting of sex-specific CYP450 expression have suggested that aromatization of testosterone to estradiol in the neonatal brain is responsible for the imprinting (Lund et al., 1991). Through a series of various endocrine manipulations, it was ultimately concluded that gonadal hormones regulate expression of some sex-specific hepatic enzymes at the hypothalamic–pituitary axis via growth hormone secretion pattern (Mode et al., 1982). Estrogen receptor (ER) in the liver is regulated via a complex interaction of growth hormone, thyroid hormones and glucocorticoids, although growth hormone is the most important (Freyschuss et al., 1994). Hypophysectomy decreases cytosolic (or weakly associated nuclear) ER in male and female rats (Dickson, & Eisenfeld, 1979, Freychuss, Sahlin, Masironi, & Eriksson, 1994). In addition, administration of growth hormone to hypophysectomized rats restores hepatic ER expression (Dickson, & Eisenfeld, 1979, Freychuss, Sahlin, Masironi, & Eriksson, 1994). Further studies have shown that estradiol can increase cytosolic ER and mRNA in male rats (Koritnik et al., 1995) and in ovariectomized female rats (Sahlin, Norstedt, & Eriksson, 1994, Sahlin, 1995). It is thought that the effects of estradiol on ER expression in the liver are indirect, resulting from changes in serum growth hormone (Sahlin, 1995).