Effect of dietary administration of genistein, nonylphenol or ethinyl estradiol on hepatic testosterone metabolism, cytochrome P-450 enzymes, and estrogen receptor alpha expression.
The objective of this study was to examine effects of estrogenic agents of varying potencies (genistein, p-nonylphenol, and ethinyl estradiol) on hepatic testosterone metabolism, cytochrome P-450 (CYP450) enzymes, and ERalpha expression. These endpoints were examined as potential biomarkers of, and contributors to, endocrine disruptive activity. Exposure occurred during critical developmental periods, from gestational day 7 through weaning via the mothers' diet. Thereafter, rats were exposed via their diet to the compounds until puberty (postnatal day 50). Testosterone hydroxylase and 5alpha-reductase activities, CYP2C and CYP3A levels were determined. In general, the compounds were more active in male rats than female rats. The only effect observed in female rats was at the 250 ppm genistein dose, in which an approximately 40% increase in 5alpha-reductase activity was observed. In male rats, genistein treatment had mixed effects on testosterone metabolism. The 1250 ppm dose decreased both CYP2C and CYP3A protein levels. Nonylphenol had the most profound effects on testosterone metabolism and CYP450 expression in male rats, with effects occurring at doses as low as 25 ppm. An increase in 5alpha-reductase activity and a decrease in the formation of 16alpha-OH-, 2alpha-OH-testosterone metabolites, CYP2C and CYP3A protein were observed. EE2 decreased the formation of several testosterone metabolites and CYP2C protein. All compounds had some effect on hepatic ERalpha expression, although a consistent effect was not observed. This study demonstrates that the test compounds can influence hepatic testosterone hydroxylase activity and CYP450 expression, as well as ERalpha expression, although these activities cannot be directly related to estrogenic activity.
Laurenzana
E M
EM
National Center for Toxicological Research, Jefferson, AR 72079, USA.
Weis
C C
CC
Bryant
C W
CW
Newbold
R
R
Delclos
K B
KB
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015415:Biomarkers; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004032:Diet; D004702:Endocrine Glands / Q000187:drug effects* / Q000378:metabolism; D047628:Estrogen Receptor alpha; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D019833:Genistein / Q000008:administration & dosage / Q000633:toxicity*; D005865:Gestational Age; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010636:Phenols / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D012741:Sexual Maturation; D013250:Steroid Hydroxylases / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D014886:Weaning
D015415:Biomarkers; D047628:Estrogen Receptor alpha; D010636:Phenols; D011960:Receptors, Estrogen; C400322:cytochrome P-450 CYP2C subfamily; D013739:Testosterone; D004997:Ethinyl Estradiol; C025256:nonylphenol; D003577:Cytochrome P-450 Enzyme System; D019833:Genistein; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C022724:testosterone 7-alpha-hydroxylase, hamster; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D010089:Oxidoreductases, N-Demethylating