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PT07 Chemical and Biological Analysis of Endocrine Disrupting Compounds
(PT108) Mechanisms of Germinal Vesicle Breakdown (GVBD) Inhibition by Substituted Glycol Ethers in Xenopus Oocytes.
Fort, D.1, Rogers, R.1, Thomas, J.1, Guiney, P.2, Weeks, J.2, 1 Fort Environmental Laboratories, Inc., Stillwater, OK, USA2 S.C. Johnson & Son, Racine, WI, USA
ABSTRACT- A 24-h in vitro Xenopus oocyte maturation assay was used to screen chemicals for potential endocrine disruption activity. Under normal conditions, Xenopus oocytes undergo final maturation which is induced by progesterone via a membrane bound receptor (OMPR) or androgens via a classical intracellular receptor (AR). Final maturation is marked morphologically by germinal vesicle breakdown (GVBD). Because the Xenopus oocyte progesterone receptor is membrane bound, chemicals in the medium may directly interact with the OMPR. The progestin/antiprogestin activities of a series of substituted glycol ethers including: ethylene glycol monomethyl ether (EGME), -monoethyl ether (EGEE), -monopropyl ether (EGPE), -monobutyl ether (EGBE), -monophenyl ether (EGPhE), diethylene glycol monomethyl ether (DGME), and triethylene glycol monomethyl ether (TGME) were screened using an in vitro Xenopus oocyte GVBD assay. Results suggested that each of the ethylene glycol ethers, but not DGME or TGME were capable of inhibiting GVBD in vitro in a concentration dependent manner with the following relative potency: EGPhE > EGME >> EGEE > EGPE >> EGBE >> DGME > TGME. Potency, expressed as an IC25, ranged from 0.001 mg/L for EGPhE to >10 mg/L for TGME. Because of the unexpected potency of EGPhE based structure activity assessment, radioreceptor OMPR binding studies with each of the glycol ethers, as well as, flutamide and androstene dione challenge studies with EGPhE were performed. Results from these studies suggested that the inhibitory effects of EGME, EGEE, EGPE, and EGBE on GVBD may be mediated primarily through the OMPR, whereas the unanticipated potency of EGPhE is postulated to be a result of bimodal inhibition of both the OMPR and AR pathways. Overall, these results suggest that the Xenopus oocyte GVBD assay could be useful in high throughput EDC screening.
Key words: oocyte, Xenopus, GVBD, glycol ethers
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