Modulation of testosterone-metabolizing hepatic cytochrome P-450 enzymes in developing Sprague-Dawley rats following in utero exposure to p,p'-DDE.
1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) causes sexual developmental aberrations in male rats through a likely mechanism of androgen receptor antagonism. DDE is also known to induce liver cytochrome P-450 (CYP). The expression of CYP enzymes is regulated by steroid hormones, which, in turn, are inactivated in the liver by CYP-catalyzed hydroxylations and subsequent conjugations. This study was undertaken to examine the potential of in utero DDE exposure to affect the developmental expression of the hepatic CYP enzymes that are responsible for testosterone hydroxylations. Pregnant Sprague-Dawley rats were dosed daily by gavage with DDE at 0, 10, or 100 mg/kg body weight or with flutamide at 40 mg/kg body weight from gestation day 14 to 18. Additional adult male rats were given seven daily doses of DDE at 100 mg/kg. Liver samples were collected from the offspring of the dosed dams on postnatal days (PND) 10 and 21 and from the adult rats a day after the last dosing. Assays for regioselective and sterospecific testosterone hydroxylase activities were performed using hepatic microsomal preparations. Specific liver CYP proteins were detected by immunoblotting. While the CYP2B1 and 3A1 and their hydroxylated testosterone products were highly elevated by the DDE treatments in both adult and developing rats, the responses of 2C11 and 2A1 were development-dependent. The flutamide treatment had little effect on CYP enzyme expression. This study demonstrated that developing offspring rats are susceptible to the hepatic CYP enzyme-modulating action of DDE following its administration to the pregnant dams.
You
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Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina, 27709-2137, USA.
Chan
S K
SK
Bruce
J M
JM
Archibeque-Engle
S
S
Casanova
M
M
Corton
J C
JC
Heck
H
H
D000367:Age Factors; D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D003633:Dichlorodiphenyl Dichloroethylene / Q000633:toxicity*; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008431:Maternal-Fetal Exchange / Q000187:drug effects*; D008862:Microsomes, Liver / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000145:classification / Q000378:metabolism*; D013997:Time Factors
D000726:Androgen Antagonists; D003633:Dichlorodiphenyl Dichloroethylene; D005485:Flutamide; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C022724:testosterone 7-alpha-hydroxylase, hamster