Ptak A, Ludewig G, Gregoraszczuk E Ł
Department of Physiology and Toxicology of Reproduction, Institute of Zoology, Jagiellonian University, Krakow, Poland.
J Physiol Pharmacol. 2008 Sep;59(3):577-88.
Polychlorinated biphenyls (PCBs) have been detected at high levels, up to hundreds of pg/ml, in human ovarian follicle fluid. The effect of PCBs on the ovary and the consequences of exposure are largely unknown. We have previously shown that PCB3 (4-chlorobiphenyl) increases the secretion of estradiol and the activity of cytochrome P450s (CYPs) in ovarian follicle cells. Our goal here is to elucidate the mechanism of CYP induction by this congener. Exposure of porcine follicle cells, a co-culture of theca and granulosa cells, to 6 ng/ml of PCB3 caused an increase in CYP1A1 protein and enzymatic activity, in the same manner as exposure to exogenous 17beta-estradiol. No changes were seen in the protein level of the aryl hydrocarbon receptor (AhR), which mediates the first step in the signaling pathway of CYP1A1 induction. However, a strong reduction was seen in the protein level of estrogen receptor beta (ERbeta), while no effect was seen on ERalpha protein levels. These result suggest that: 1) PCB3 acts as an agonist of ERbeta but not the Ah receptor in the ovarian follicles, 2) PCB3 is not only an efficacious inducer of CYP1A1 expression and activity, but also a substrate for this enzyme. Changes in the expression level of CYP1A1 not only alter the intensity of the activity of PCB3, but also the activity of estrogen in the ovary.
在人类卵巢卵泡液中已检测到高浓度的多氯联苯（PCBs），高达数百皮克/毫升。PCBs对卵巢的影响以及暴露的后果在很大程度上尚不清楚。我们之前已经表明，PCB3（4-氯联苯）可增加卵巢卵泡细胞中雌二醇的分泌以及细胞色素P450s（CYPs）的活性。我们在此的目标是阐明该同系物诱导CYP的机制。将猪卵泡细胞（卵泡膜细胞和颗粒细胞的共培养物）暴露于6纳克/毫升的PCB3中，会导致CYP1A1蛋白和酶活性增加，其方式与暴露于外源性17β-雌二醇相同。介导CYP1A1诱导信号通路第一步的芳烃受体（AhR）的蛋白水平未见变化。然而，雌激素受体β（ERβ）的蛋白水平大幅降低，而对ERα蛋白水平未见影响。这些结果表明：1）PCB3在卵巢卵泡中作为ERβ的激动剂而非Ah受体起作用；2）PCB3不仅是CYP1A1表达和活性的有效诱导剂，也是该酶的底物。CYP1A1表达水平的变化不仅改变了PCB3的活性强度，也改变了卵巢中雌激素的活性。
