Patnode K A, Curtis L R
Oak Creek Laboratory of Biology, Department of Fisheries and Wildlife, Oregon State University, Corvallis 97331.
Toxicol Appl Pharmacol. 1994 Jul;127(1):9-18. doi: 10.1006/taap.1994.1133.
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.
雌性水貂（鼬属水貂）对有机氯（OC）诱导的生殖损伤高度敏感。然而，这种生殖毒性的机制尚不清楚。我们研究了类固醇受体在胚胎毒性和新生幼崽体重减轻中可能发挥的作用。将处于动情间期的幼年雌性水貂和怀孕的成年水貂暴露于共平面多氯联苯（PCB）3,3',4,4',5,5'-六氯联苯（3HCB）或非共平面PCB同系物2,2',4,4',5,5'-六氯联苯（2HCB）中。两种同系物均损害了动情间期水貂经腹腔注射100微克β-雌二醇（E2β）24小时后子宫核雌激素受体（ERn）的上调。暴露于0.4毫克3HCB/千克>0.8毫克3HCB/千克>20毫克2HCB/千克14天后首次观察到胚胎毒性和胚胎生长减缓。在怀孕水貂中，所有3HCB处理均显著增加了孕酮受体解离常数（PR Kd）。20毫克2HCB/千克>0.8毫克3HCB/千克可增加ER浓度和PR总受体数（Rt），但0.4毫克3HCB/千克对其无影响。血清E2β低于检测限。2HCB可增加孕酮（P）浓度，0.8毫克3HCB/千克可降低P浓度，0.4毫克3HCB/千克对P浓度无影响。3HCB可使处于动情间期的水貂肝脏细胞色素P450（P450）诱导1.8倍，使怀孕水貂诱导2.2倍。乙氧基异吩恶唑酮-O-脱乙基酶（EROD）在处于动情间期和怀孕的水貂中分别诱导13倍和4倍。暴露于2HCB会导致处于动情间期的幼年水貂P450浓度降低，但在妊娠期间对P450或任何时候的EROD活性均无影响。我们认为胚胎毒性和胚胎生长迟缓是由PR功能受损导致的，并且HCB处理效果的差异是其剂量依赖性部分雌激素作用的结果，这种作用通过上调ER增加PR Rt。
