INRS-Institut Armand-Frappier, Université du Québec, 531 blv des Prairies, Laval, QC, Canada H7V 1B7.
Toxicol Appl Pharmacol. 2010 Nov 15;249(1):33-40. doi: 10.1016/j.taap.2010.08.011. Epub 2010 Aug 17.
Dysfunction of the enzyme aromatase (CYP19) is associated with endocrine pathologies such as osteoporosis, impaired fertility and development of hormone-dependent cancers. Certain endocrine disrupting chemicals affect aromatase expression and activity in vitro, but little is known about their ability to do so in vivo. We evaluated a bioluminescent mouse model (LPTA®)CD-1-Tg(Cyp19-luc)-Xen) expressing luciferase under control of the gonadal aromatase pII promoter as an in vivo screening tool for chemicals that may affect aromatase expression. We studied the effects of forskolin, pregnant mare serum gonadotropin and atrazine in this model (atrazine was previously shown to induced pII-promoter-driven aromatase expression in H295R human adrenocortical carcinoma cells). About 2-4 out of every group of 10 male or female Cyp19-luc mice injected i.p. with 10 mg/kg forskolin had increased gonadal bioluminescence after 3-5 days compared to controls; the others appeared non-responsive. Similarly, about 4 per group of 9 individual females injected with pregnant mare serum gonadotropin had increased ovarian bioluminescence after 24 h. There was a statistically significant correlation between ovarian bioluminescence and plasma estradiol concentrations (n=14; p=0.022). Males exposed to a single dose of 100 mg/kg or males and females exposed to 5 daily injections of 30 mg/kg atrazine showed no change in gonadal bioluminescence over a 7 day period, but a significant interaction was found between atrazine (100 mg/kg) and time in female mice (p<0.05; two-way ANOVA). Ex vivo luciferase activity in dissected organs was increased by forskolin in testis, epididymis and ovaries. Atrazine (30 mg/kg/day) increased (30%) luciferase activity significantly in epididymis only. In conclusion, certain individual Cyp19-luc mice are highly responsive to aromatase inducers, suggesting this model, with further optimization, may have potential as an in vivo screening tool for environmental contaminants.
芳香酶（CYP19）的功能障碍与内分泌病理学有关，如骨质疏松症、生育能力受损和激素依赖性癌症的发展。某些内分泌干扰化学物质会影响体外芳香酶的表达和活性，但对它们在体内的这种能力知之甚少。我们评估了一种生物发光小鼠模型（LPTA®）CD-1-Tg（Cyp19-luc）-Xen），其在性腺芳香酶 pII 启动子的控制下表达荧光素酶，作为一种可能影响芳香酶表达的化学物质的体内筛选工具。我们在该模型中研究了 forskolin、孕马血清促性腺激素和莠去津的作用（先前的研究表明莠去津在 H295R 人肾上腺皮质癌细胞中诱导了 pII 启动子驱动的芳香酶表达）。大约每 10 只雄性或雌性 Cyp19-luc 小鼠中，有 2-4 只经腹腔注射 10mg/kg forskolin 3-5 天后与对照组相比，性腺生物发光增加；其余的似乎没有反应。同样，大约每 9 只接受孕马血清促性腺激素注射的雌性个体中，有 4 只在 24 小时后卵巢生物发光增加。卵巢生物发光与血浆雌二醇浓度之间存在统计学显著相关性（n=14；p=0.022）。单次暴露于 100mg/kg 莠去津或每日接受 5 次 30mg/kg 莠去津注射的雄性和雌性小鼠在 7 天期间，性腺生物发光没有变化，但在雌性小鼠中发现莠去津（100mg/kg）和时间之间存在显著相互作用（p<0.05；双因素方差分析）。在离体器官中， forskolin 增加了睾丸、附睾和卵巢中的荧光素酶活性。仅莠去津（30mg/kg/天）显著增加了附睾中的荧光素酶活性（30%）。总之，某些 Cyp19-luc 小鼠对芳香酶诱导剂高度敏感，这表明该模型在进一步优化后可能具有作为体内筛选环境污染物的工具的潜力。
