Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Environ Toxicol Pharmacol. 2005 May;19(3):761-5. doi: 10.1016/j.etap.2004.12.055. Epub 2005 Feb 17.
Recently, we reported on in vitro and in vivo estrogenic activity of UV filters and on developmental toxicity of 4-methylbenzylidene (4-MBC) camphor [Schlumpf, M., Cotton, B., Conscience, M., Haller, V., Steinmann, B., Lichtensteiger, W., 2001a. In vitro and in vivo estrogenicity of UV screens. Environ. Health Perspect. 109, 239; Schlumpf, M., Berger, L., Cotton, B., Conscience-Egli, M., Durrer, S., Fleischmann, I., Haller, V., Maerkel, K., Lichtensteiger, W., 2001b. Estrogen active UV screens. SÖFW-J. 7, 10]. 4-MBC (7, 24, 47mg/(kgday)) was administered in chow to long Evans rats from 10 weeks before mating of the parent (F0) generation until adulthood of the F1 generation. Peripheral reproductive organs and central nervous system were studied in adult offspring. mRNA expression of progesterone receptor (PR), an estrogen-regulated gene, was investigated in medial preoptic area (MPO) and ventromedial hypothalamic nucleus (VMH) by real-time RT-PCR. We analyzed intact 12-week-old male and female offspring under steady state conditions and adult gonadectomized offspring 6h after a single s.c. injection of estradiol-17β (E2) (10 or 50μg/kg) in order to assess estrogen sensitivity. At steady state conditions we observed significantly higher PR mRNA expression in VMH of control females versus control males. 4-MBC exposed females exhibited a decrease in PR mRNA to levels of control males. The increase in PR mRNA in response to E2 was higher in VMH of males of both 4-MBC groups as compared to control males. PR mRNA levels were similar in MPO of control males and females. Developmental 4-MBC exposure increased PR mRNA levels in male MPO, but did not significantly change female levels. The acute response to the lower E2 dose was decreased in MPO of 4-MBC-exposed males, whereas females of the 7mg/kg dose group exhibited an increased reaction to 50μg/kg of E2. Our data indicate that developmental exposure to endocrine active chemicals such as the UV filter 4-MBC can interfere with sexually dimorphic gene expression in brain in a sex- and region-specific manner.
最近，我们报道了紫外线滤光剂的体外和体内雌激素活性，以及 4-甲基苯亚甲基樟脑（4-MBC）的发育毒性[Schlumpf，M.，Cotton，B.，Conscience，M.，Haller，V.，Steinmann，B.，Lichtensteiger，W.，2001a.UV 屏幕的体外和体内雌激素活性。环境健康透视。109，239；Schlumpf，M.，Berger，L.，Cotton，B.，Conscience-Egli，M.，Durrer，S.，Fleischmann，I.，Haller，V.，Maerkel，K.，Lichtensteiger，W.，2001b.雌激素活性 UV 屏幕。SÖFW-J.7，10]。4-MBC（7、24、47mg/（kg·天））以饲料形式给予长 Evans 大鼠，从亲代（F0）代的交配前 10 周开始，直至 F1 代成年。研究了成年后代的外周生殖器官和中枢神经系统。通过实时 RT-PCR 研究了中脑前视区（MPO）和腹内侧下丘脑核（VMH）中孕激素受体（PR）的 mRNA 表达，孕激素受体是一种受雌激素调节的基因。我们分析了处于稳定状态的 12 周龄雄性和雌性未成熟后代，以及在单次皮下注射 17β-雌二醇（E2）（10 或 50μg/kg）后 6 小时的成年去势后代，以评估雌激素敏感性。在稳定状态下，我们观察到对照雌性的 VMH 中 PR mRNA 的表达明显高于对照雄性。暴露于 4-MBC 的雌性 PR mRNA 下降至对照雄性水平。与对照组雄性相比，两组 4-MBC 暴露的雄性 VMH 中 PR mRNA 的增加更为明显。对照组雄性和雌性 MPO 中的 PR mRNA 水平相似。发育性 4-MBC 暴露增加了雄性 MPO 中的 PR mRNA 水平，但对雌性水平没有显著影响。4-MBC 暴露雄性 MPO 对低剂量 E2 的急性反应降低，而 7mg/kg 剂量组的雌性对 50μg/kg 的 E2 反应增强。我们的数据表明，暴露于紫外线滤光剂等内分泌活性化学物质可能会以性别和区域特异性的方式干扰大脑中性别二态基因的表达。
