Comparison of the actions of 4-chlorobiphenyl and its hydroxylated metabolites on estradiol secretion by ovarian follicles in primary cells in culture

Theca interna and granulosa cells from small, medium and large preovulatory porcine follicles were cultured as a monolayer to compare the effects of 4-chlorobiphenyl (PCB3) and its metabolites on estradiol secretion. Cells were treated with PCB3 or its mono- and di-hydroxylated metabolites 4-OH-PCB3 and 3,4-di-OH-PCB3 at concentrations of 0.06, 0.6, 6 and 60 ng/ml medium for 24 h. Each compound significantly increased estradiol levels detected in the medium of small, medium and large follicle cultures. This effect was evident at even the lowest concentration tested (0.06 ng/ml). A time-series with 6.0 ng/ml PCB3 or metabolites showed estrogenic action at each test interval (24, 48, 72, 96 h) and established a rankorder potency of 3,4-OH-PCB>4-OH-PCB3>or=PCB3. In small and medium follicles treated with PCB3 metabolites the temporal increase led to estradiol accumulations >20,000-fold over control culture media. Large preovulatory follicles had the highest estrogenic action at 72 h of exposure, decreasing somewhat at 96 h. These findings indicate that PCB3 and its hydroxylated metabolites induce a surge in estradiol secretion in ovarian follicle cells. Such a response would in vivo be expected to disrupt reproductive processes, through enhanced aging of the follicle and negative feedback to the hypothalamus, and perhaps increase the risk for ovarian and breast cancer.