首页> 外文期刊>Breast Cancer Research and Treatment >Long-term Effects of the Mammary Carcinogen 7,12-Dimethylbenz(a) Anthracene on Hypothalamic Gonadotropin-Releasing Hormone and its Pituitary Receptor Gene Expression, During the Promotion Stage, in Female Sprague-Dawley Rats
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Long-term Effects of the Mammary Carcinogen 7,12-Dimethylbenz(a) Anthracene on Hypothalamic Gonadotropin-Releasing Hormone and its Pituitary Receptor Gene Expression, During the Promotion Stage, in Female Sprague-Dawley Rats

机译:雌性Sprague-Dawley大鼠在促进阶段,乳腺致癌物7,12-二甲基苯并(a)蒽对下丘脑促性腺激素释放激素及其垂体受体基因表达的长期影响

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摘要

A single intragastric administration of 7,12-dimethylbenz(a)anthracene (DMBA) has been shown to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of these tumors is preceded by a series of neuroendocrine disturbances, including attenuation of the preovulatory luteinizing hormone (LH) surge and amplification of the preovulatory 17β-estradiol surge, and gonadotropin-releasing hormone (GnRH) released in vitro. In this study, we examined the hypothesis that DMBA administration decreases levels of GnRH mRNA in the preoptic area-anterior hypothalamus (POA-AH) and GnRH receptor (GnRH Rc) mRNA and protein in the anterior pituitary gland. Sprague-Dawley rats, 55–60 days of age with regular estrous cycles, received a single dose of 15 mg DMBA in 1 ml sesame oil delivered by intragastric intubation. A first series of experiments was performed for the measurement of hypothalamic GnRH mRNA and pituitary GnRH Rc mRNA levels. A second series of experiments was performed for the measurement of pituitary GnRH receptor. In both experiments, animals were sacrificed by decapitation at 11.00, 16.00, 18.00 and 20.00 h on each day of the 7th or 8th estrous cycle (28–32 days) after treatment. GnRH and GnRH receptor mRNAs were quantified using solution hybridization-RNase protection assay. The GnRH Rc was quantified using the 125I-D-Ala6-N-Met-Leu6-des-Gly10-ethylamide GnRH. DMBA-treatment produced no significant effect on the overall mean values of GnRH mRNA. GnRH mRNA levels in control rats rose significantly between 16.00 and 20.00 h on proestrus and between 18.00 and 20.00 h on diestrus I. DMBA-treated rats had a surge in GnRH mRNA levels at 18.00 h on proestrus, and showed additional surges at 18.00 h on diestrus II and estrus. GnRH receptor mRNA content in the anterior pituitary gland surged at 16.00 h on certain days of the cycle in both groups of rats. In control rats, only the surge on diestrus II proved significant, whereas DMBA-treated rats exhibited significant surges on diestrus I, diestrus II and proestrus. GnRH receptor mRNA values were significantly lower on both days of diestrus in DMBA-treated rats compared with controls. GnRH Rc peptide content, like GnRH receptor in RNA surged at 16.00 h in both groups with the exception of a marked fall on proestrus day for DMBA treated rats. A reduction in the amplitude of the surge was also seen on the day of estrous and to a lesser extend on the day of diestrus DII in DMBA treated animal. Overall, there was a disruption of the GnRH Rc pattern which culminate on the day of proestrus in DMBA-treated animals. Interestingly, the daily rise between 11.00 and 16.00 h which is the more pronounced on the day of proestrus in control animals, was completely blunted in DMBA-treated rats. Overall, the results are consistent with the hypothesis that the carcinogen attenuates, directly or indirectly, preovulatory biosynthesis of the GnRH receptor and LH release.
机译:已显示单次胃内给药7,12-二甲基苯并(a)蒽(DMBA)会在年轻的单车雌性Sprague-Dawley大鼠中诱发乳腺肿瘤。这些肿瘤的出现之前会发生一系列神经内分泌紊乱,包括排卵前黄体生成激素(LH)增高的衰减和排卵前17β-雌二醇增高的放大,以及促性腺激素释放激素(GnRH)的体外释放。在这项研究中,我们检查了以下假设,即DMBA给药可降低垂体前区-垂体前下丘脑(POA-AH)中的GnRH mRNA水平和垂体前腺中的GnRH受体(GnRH Rc)mRNA和蛋白水平。 55-60天大的Sprague-Dawley大鼠有规律的发情周期,在通过胃内插管递送的1 ml麻油中接受了15 mg DMBA单剂。进行了第一系列实验,用于测量下丘脑GnRH mRNA和垂体GnRH Rc mRNA水平。进行第二系列实验以测量垂体GnRH受体。在这两个实验中,在治疗后第7或第8个发情周期的每一天(28-32天),在11.00、16.00、18.00和20.00 h处死动物头以处死动物。 GnRH和GnRH受体mRNA使用溶液杂交-RNase保护试验定量。使用125 I-D-Ala6 -N-Met-Leu6 -des-Gly10 -乙酰胺GnRH定量GnRH Rc。 DMBA处理对GnRH mRNA的总体平均值无明显影响。对照大鼠的GnRH mRNA水平在发情前期在16.00和20.00 h之间以及在二重肌I上在18.00和20.00 h之间显着上升。DMBA处理的大鼠在发情前期18.00 h时GnRH mRNA水平升高,并且在18.00 h时又出现了激增。二代发情和发情。两组大鼠在周期的某些天,垂体前叶中GnRH受体的mRNA含量在16.00 h时均升高。在对照大鼠中,仅二头肌II的激增被证明是显着的,而DMBA处理的大鼠对二头肌I,二代Istruts和发情期表现出显着的激增。与对照组相比,在DMBA治疗的大鼠中,两天的GnRH受体mRNA值均显着降低。两组中的GnRH Rc肽含量(如RNA中的GnRH受体)在16.00 h均激增,但DMBA处理的大鼠在发情日明显下降。在DMBA处理的动物中,发情当天也观察到了波动幅度的减小,而在二重奏DII当天表现出较小程度的延长。总体而言,GnRH Rc模式发生了破坏,最终在DMBA治疗的动物的发情日达到高潮。有趣的是,在接受DMBA治疗的大鼠中,每天11.00至16.00 h之间的升高(在对照动物的发情日更为明显)被完全抑制了。总体而言,该结果与以下假设一致:致癌物直接或间接削弱了排卵前GnRH受体的生物合成和LH释放。

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