Induction of hepatic aromatase by p,p '-DDE in adult male rats

1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE, DDE) is a stable me tabolite of the pesticide DDT and a persistent environmental pollutant. Ear lier reports have demonstrated that DDE is an endocrine-active compound cap able of affecting early-stage sexual differentiation in male rats. Experime nts based on receptor binding affinity and receptor-mediated transcriptiona l activation have identified DDE as an androgen receptor antagonist. Other. effects of DDE include modulation of the expression and activity of cytoch rome P450 (CYP) enzymes, some of which function as steroid hydroxylases, an d elevation of serum estrogen levels in treated male rats. These effects su ggest the possibility of DDE-caused induction of aromatase, a member of CYP family that catalyzes the conversion of C19 steroids to estrogens, The pre sent study was conducted to determine whether hepatic aromatase was respons ive to DDE treatment. We found that hepatic aromatase protein in adult male rats was greatly increased after seven daily oral treatments of DDE at a d osage of 100 mg/kg wt. per day. This induction was seen in both immunoblot and immunohistochemistry of liver tissue sections. Distribution of the arom atase in the liver corresponded to the distribution of hypertrophic hepatoc ytes in the tissue. Furthermore, eve found a large increase in hepatic micr osomal aromatase activity in DDE-treated animals, although the difference i n serum 17 beta -estradiol concentrations between treated animals and contr ols was not statistically significant. However, an in vitro experiment usin g primary culture of rat hepatocytes did not show a change in aromatase lev el after DDE treatment at four concentrations ranging from 0 to 5 x 10(-6) M for 24 h. Meanwhile, CYP 2B1 induction, a known DDE effect in primary rat hepatocyte culture, was seen in those cells. This study supports the notio n that induction of aromatase by DDE is a contributory factor to its reprod uctive developmental effects. (C) 2001 Elsevier Science Ireland Ltd. All ri ghts reserved.