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  • The potent estrogen EE induced

    2019-09-24

    The potent 001 2 pathway EE2 induced a decrease in CYP2C11 activity (reduction in 2α-OH and 16α-OH testosterone) and protein at the 200 ppb dose and in this respect was similar to nonylphenol and genistein. This result agrees qualitatively with the results of Hallstrom et al. (1996) who exposed male rats to higher doses of EE2 (160–210 μg/kg/day vs approximately 45 μg/kg/day in the present study) via subcutaneous implants. On the other hand, unlike the exposures to nonylphenol and genistein, no significant effects on 5α-reductase or CYP3A were observed in the EE2-treated animals. EE2 may be covalently binding CYP2C11, resulting in degradation of the enzyme, rather than regulating expression of the enzyme. Indeed, early studies suggested that EE2 causes loss of CYP450 in 001 2 pathway the rat liver in vitro and in vivo (White and Müller-Eberhard, 1977), presumably due to mechanism-based inactivation with subsequent destruction of CYP450 (Ortiz de Montellano et al., 1979). The decrease in the female-predominant 7α-OH testosterone metabolite observed at the 25 and 200 ppb EE2 doses in our studies further argues against feminization and for destruction of CYP450. Nevertheless, it is noteworthy that the 200 ppb EE2 dose did have effects in the males in these studies (e.g. decreased testes weight, stimulation of male mammary gland, mineralization of renal tubules; Delclos et al., unpublished) that could be related to estrogenic activity and that were equivalent or more pronounced than the potentially estrogenic effects of genistein (Delclos et al., 2001) and nonylphenol (unpublished data) in males. The mechanism for the observed effects of the test compounds on 5α-reductase and CYP450 activities and expression cannot be determined without further study. It is possible that nonylphenol and genistein feminize CYP450 expression and activity via action at the hypothalamic–pituitary axis to modulate growth hormone production; however, other explanations are possible. In the case of nonylphenol, for example, rats of both sexes receiving the highest dose of nonylphenol in our studies exhibited body weights approximately 25% lower than controls at necropsy (Latendresse et al., 2001). [Rats from the high dose groups in the genistein and EE2 studies also had body weights lower than controls at sacrifice; however, the decrements were not as pronounced (∼10%, data not shown)]. In addition, a separate examination of the kidneys from the rats used in the current study revealed a severe polycystic kidney disease at the 2000 ppm dose of nonylphenol (Latendresse et al., 2001). Given the reduced weight and polycystic kidney disease, it is likely that glucocorticoid levels were increased in these nonylphenol-treated rats, although levels were not measured. Previous studies have demonstrated that glucocorticoids can suppress expression of CYP2C11 at concentrations relevant to stress conditions (Iber et al., 1997). Thus, at the 2000 ppm nonylphenol dose, glucocorticoids could play a role in the alterations in hepatic CYP450 expression. It is noteworthy, however, that some of the effects of nonylphenol on CYP450 activity and expression are seen at doses that did not cause decreased body weight or polycystic kidney disease. ER is expressed at similar levels in both male and female rat liver cytosol (approximately 2 fmol/mg liver for Sprague–Dawley rats; Dickson and Eisenfeld, 1979), and is thought to play a role in regulation of coagulation, blood pressure, and cholesterol metabolism (Lax, 1987) and may also be important during pregnancy (Eisenfeld and Aten, 1987). As previously discussed, ER in the liver is primarily regulated by growth hormone, and to a lesser extent by thyroid hormone and glucocorticoids (Freyschuss et al., 1994). In addition, it has been shown that administration of estradiol increases cytosol-associated (or loosely associated nuclear) ER protein in male rats and in ovariectomized female rats via increased synthesis (Sahlin, Norstedt, & Eriksson, 1994, Koritnik, Koshy, & Hoversland, 1995, Sahlin, 1995). Thus in our studies, increases in cytosol-associated ERα were assumed to be due to increases in synthesis, although we have not determined mRNA levels to confirm this.