2,2',4,4',5,5'- and 3,3',4,4',5,5'-hexachlorobiphenyl alteration of uterine progesterone and estrogen receptors coincides with embryotoxicity in mink (Mustela vision).
Female mink (Mustela vison) are highly sensitive to organochlorine (OC)-induced reproductive impairment. However, mechanisms of this reproductive toxicity are unknown. We have investigated the possible role of steroid receptors in embryotoxicity and reduced neonate weights. Anestrous, juvenile female mink and pregnant adult mink were exposed to 3,3',4,4',5,5'-hexachlorobiphenyl (3HCB), a coplanar polychlorinated biphenyl (PCB), or 2,2',4,4',5,5'-hexachlorobiphenyl (2HCB), a noncoplanar PCB congener. Both congeners impaired 17 beta-estradiol-stimulated (24 hr after ip administration of 100 micrograms E2 beta ip) up-regulation of uterine nuclear estrogen receptors (ERn) in anestrous mink. Embryotoxicity and reduced embryo growth were first observed 14 days after exposure to 0.4 mg 3HCB/kg > 0.8 mg 3HCB/kg > 20 mg 2HCB/kg. In pregnant mink, all 3HCB treatments significantly increased progesterone receptor dissociation constants (PR Kd). ER concentration and PR total receptor number (Rt) were increased by 20 mg 2HCB/kg > 0.8 mg 3HCB/kg, but were unaffected by 0.4 mg 3HCB/kg. Serum E2 beta was below assay detection limits. Progesterone (P) concentrations were increased by 2HCB, decreased by 0.8 mg 3HCB/kg, and unchanged by 0.4 mg 3HCB/kg. Hepatic cytochrome P450 (P450) was induced 1.8-fold in anestrous and 2.2-fold in pregnant mink by 3HCB. Ethoxyresorufin-O-deethylase (EROD) was induced 13- and 4-fold in anestrous and pregnant mink, respectively. 2HCB exposure resulted in decreased P450 concentration in anestrous juveniles, but had no effect on P450 during gestation or EROD activity at any time. We propose that embryotoxicity and retarded embryo growth result from impairment of PR function and that differences in the efficacy of HCB treatments are a result of their dose-dependent, partial estrogenic actions which increase PR Rt via up-regulation of ER.
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Oak Creek Laboratory of Biology, Department of Fisheries and Wildlife, Oregon State University, Corvallis 97331.
Curtis
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D000818:Animals; D000831:Animals, Newborn; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020964:Embryo Loss / Q000139:chemically induced*; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D008907:Mink / Q000196:embryology; D010088:Oxidoreductases / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D011374:Progesterone / Q000097:blood; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011374:Progesterone; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; C027309:3,4,5,3',4',5'-hexachlorobiphenyl; C014024:2,4,5,2',4',5'-hexachlorobiphenyl