2,2',4,4',5,5'-HEXACHLOROBIPHENYL AND 3,3',4,4',5,5'-HEXACHLOROBIPHENYL ALTERATION OF UTERINE PROGESTERONE AND ESTROGEN-RECEPTORS COINCIDESWITH EMBRYOTOXICITY IN MINK (MUSTELA-VISON)

Female mink (Mustela vison) are highly sensitive to organochlorine (OC )-induced reproductive impairment. However, mechanisms of this reprodu ctive toxicity are unknown. We have investigated the possible role of steroid receptors in embryotoxicity and reduced neonate weights. Anest rous, juvenile female mink and pregnant adult mink were exposed to 3,3 ',4,4',5,5'-hexachlorobiphenyl (3HCB), a coplanar polychlorinated biph enyl (PCB), or 2,2',4,4',5,5'-hexachlorobiphenyl (2HCB), a noncoplanar PCB congener. Both congeners impaired 17 beta-estradiol-stimulated (2 4 hr after ip administration of 100 mu g E(2) beta ip) up-regulation o f uterine nuclear estrogen receptors (ERn) in anestrous mink. Embryoto xicity and reduced embryo growth were first observed 14 days after exp osure to 0.4 mg 3HCB/kg > 0.8 mg 3HCB/kg > 20 mg 2HCB/kg. In pregnant mink, all 3HCB treatments significantly increased progesterone recepto r dissociation constants (PR K-d). ER concentration and PR total recep tor number (R(t)) were increased by 20 mg 2HCB/kg > 0.8 mg 3HCB/kg, bu t were unaffected by 0.4 mg 3HCB/kg. Serum E(2) beta was below assay d etection limits. Progesterone (P) concentrations were increased by 2HC B, decreased by 0.8 mg 3HCB/kg, and unchanged by 0,4 mg 3HCB/kg. Hepat ic cytochrome P450 (P450) was induced 1.8-fold in anestrous and 2.2-fo Id in pregnant mink by 3HCB. Ethoxyresorufin-O-deethylase (EROD) was i nduced 13- and 4-fold in anestrous and pregnant mink, respectively. 2H CB exposure resulted in decreased P450 concentration in anestrous juve niles, but had no effect on P450 during gestation or EROD activity at any time. We propose that embryotoxicity and retarded embryo growth re sult from impairment of PR function and that differences in the effica cy of HCB treatments are a result of their dose-dependent, partial est rogenic actions which increase PR R(t) via up-regulation of ER. (C) 19 94 Academie Press, Inc.