Models Assessing Direct Effects of Dioxins and Related Compounds on the OvaryEPA Grant Number: R826132
Title: Models Assessing Direct Effects of Dioxins and Related Compounds on the Ovary
Investigators: Terranova, Paul F.
Institution: University of Kansas Medical Center
EPA Project Officer: Klieforth, Barbara I
Project Period: October 1, 1997 through September 30, 2000
Project Amount: $597,855
RFA: Endocrine Disruptors (1997) RFA Text | Recipients Lists
Research Category: Endocrine Disruptors , Economics and Decision Sciences , Health , Safer Chemicals
Previous studies in rats have indicated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has inhibitory effects on ovulation and this action may be the result of either direct effects of TCDD on ovarian function or via alteration in pituitary gonadotropins that regulate ovarian follicular development, steroidogenesis and ovulation. The objectives of this study are to investigate whether TCDD, other dioxins, furans and polychlorinated biphenyls (PCBs) directly affect ovarian function using the hypophysectomized rat as an in vivo model.
The approaches used in this study to meet our objectives are four-fold. First, the effects of TCDD in vivo on changes in gonadotropin receptor binding, second messengers, and steroid production will be evaluated on theca-interstitial cells of immature hypophysectomized rats; this will elucidate the mechanism by which TCDD modulates thecal cell function in vivo. Secondly, the effects of TCDD in vitro on changes in gonadotropin receptor binding, second messengers and steroid production will be evaluated on ovarian theca-interstitial cells. Thirdly, the in vivo effects of TCDD on: a) follicular development in immature hypophysectomized rats exposed to physiologic doses of gonadotropin, b) the steroidogenic responses of the ovary to gonadotropin and c) ovulation induction and corpora luteal function controlled by gonadotropin. The fourth aim is to determine if other dioxins, furans and polychlorinated biphenyls, have the same mode of direct action on ovarian function using ovulation and steroidogenesis as biomarkers, and to demonstrate that this model can be used for the assessment of toxic equivalency factors (TEFs). It is our intention in the fourth aim that a mixture of dioxins, furans and PCBs with different potencies will be made up based on the results of the aforementioned experiments, and then its total potency (each congener contributes to the toxicity of the mixture in accordance with its relative potency) will be tested.
We expect to find that dioxin has direct inhibitory effects on ovarian function. Thecal cells within the ovary are expected to be the target of the dioxin and related compounds. Although we do not expect follicular development to be altered by these compounds, we do expect that ovulation will be blocked. In addition, it is expected that ovarian steroidogenesis will be altered and this may serve as the underlying basis for blockage of ovulation. It is expected that this model will serve as new means of testing endocrine disruption and toxicity in not only the ovary but other endocrine organs.