Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA.
Toxicol Appl Pharmacol. 2012 Oct 1;264(1):1-12. doi: 10.1016/j.taap.2012.07.031. Epub 2012 Aug 6.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent ovarian toxicant. Previously, we demonstrated that in vitro TCDD (1nM) exposure decreases production/secretion of the sex steroid hormones progesterone (P4), androstenedione (A4), testosterone (T), and 17β-estradiol (E2) in mouse antral follicles. The purpose of this study was to determine the mechanism by which TCDD inhibits steroidogenesis. Specifically, we examined the effects of TCDD on the steroidogenic enzymes, atresia, and the aryl hydrocarbon receptor (AHR) protein. TCDD exposure for 48h increased levels of A4, without changing HSD3B1 protein, HSD17B1 protein, estrone (E1), T or E2 levels. Further, TCDD did not alter atresia ratings compared to vehicle at 48h. TCDD, however, did down regulate the AHR protein at 48h. TCDD exposure for 96h decreased transcript levels for Cyp11a1, Cyp17a1, Hsd17b1, and Cyp19a1, but increased Hsd3b1 transcript. TCDD exposure particularly lowered both Hsd17b1 transcript and HSD17B1 protein. However, TCDD exposure did not affect levels of E1 in the media nor atresia ratings at 96h. TCDD, however, decreased levels of the proapoptotic factor Bax. Collectively, these data suggest that TCDD exposure causes a major block in the steroidogenic enzyme conversion of A4 to T and E1 to E2 and that it regulates apoptotic pathways, favoring survival over death in antral follicles. Finally, the down-regulation of the AHR protein in TCDD exposed follicles persisted at 96h, indicating that the activation and proteasomal degradation of this receptor likely plays a central role in the impaired steroidogenic capacity and altered apoptotic pathway of exposed antral follicles.
2,3,7,8-四氯二苯并对二恶英（TCDD）是一种有效的卵巢毒物。以前，我们证明了在体外 TCDD（1nM）暴露会降低小鼠腔前卵泡中性激素孕激素（P4）、雄烯二酮（A4）、睾酮（T）和 17β-雌二醇（E2）的产生/分泌。本研究的目的是确定 TCDD 抑制类固醇生成的机制。具体来说，我们研究了 TCDD 对类固醇生成酶、闭锁和芳香烃受体（AHR）蛋白的影响。TCDD 暴露 48h 后，A4 水平升高，但 HSD3B1 蛋白、HSD17B1 蛋白、雌酮（E1）、T 或 E2 水平不变。此外，与载体相比，TCDD 在 48h 时并未改变闭锁评分。然而，TCDD 在 48h 时下调了 AHR 蛋白。TCDD 暴露 96h 降低了 Cyp11a1、Cyp17a1、Hsd17b1 和 Cyp19a1 的转录水平，但增加了 Hsd3b1 的转录水平。TCDD 暴露尤其降低了 Hsd17b1 转录本和 HSD17B1 蛋白。然而，TCDD 暴露并未影响 96h 时培养基中 E1 的水平或闭锁评分。然而，TCDD 降低了促凋亡因子 Bax 的水平。总的来说，这些数据表明，TCDD 暴露导致 A4 向 T 和 E1 向 E2 的类固醇生成酶转化中出现严重阻滞，并且它调节凋亡途径，有利于腔前卵泡的存活而不是死亡。最后，在 TCDD 暴露的卵泡中，AHR 蛋白的下调持续到 96h，表明该受体的激活和蛋白酶体降解可能在暴露的腔前卵泡类固醇生成能力受损和凋亡途径改变中发挥核心作用。
