2-chloro-s-triazine herbicides induce aromatase (CYP19) activity in H295R human adrenocortical carcinoma cells: A novel mechanism for estrogenicity?

There is increasing concern that certain chemicals in the environment can c ause endocrine disruption in exposed humans and wildlife. Investigations of potential effects on endocrine function have been limited mainly to intera ctions with hormone receptors. A need exists for the development of alterna te in vitro methods to evaluate chemicals for their potential to disturb va rious endocrine functions via other mechanisms. Our laboratory is using the human H295R adrenocortical carcinoma cell line to examine chemicals for th eir potential to interfere with the activity and/or expression of several k ey cytochrome P450 (CYP) enzymes involved in the biosynthesis of steroid ho rmones. In this report we demonstrated that the commonly used 2-chloro-s-tr iazine herbicides atrazine, simazine, and propazine dose-dependently (0-30 mu M) induced aromatase (CYP19) activity to an apparent maximum of about 2. 5-fold in H295R cells. Basal- and triazine-induced aromatase activity was c ompletely inhibited by the irreversible aromatase inhibitor 4-hydroxyandros tenedione (100 mu M). The triazines increased levels of CYP19 messenger rib onucleic acid (mRNA) between 1.5- and 2-fold. The time-response profile of the induction of aromatase activity and CYP19 mRNA by the triazines was sim ilar to that by 8-bromo-cyclic adenosine monophosphate, a known stimulant o f the protein kinase-A pathway that mediates the induction of aromatase in these cells. The observed induction of aromatase, the rate-limiting enzyme in the conversion of androgens to estrogens, may be an underlying explanati on for some of the reported hormonal disrupting and tumor promoting propert ies of these herbicides in vivo.