College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou, 310032, PR China.
Comp Biochem Physiol C Toxicol Pharmacol. 2011 May;153(4):392-401. doi: 10.1016/j.cbpc.2011.01.003. Epub 2011 Jan 31.
The study of endocrine disruption is being increasingly conducted at the mRNA level of genes, as this approach might yield insight into the modes of action and mechanisms of toxicity. In this study, the transcriptional responses of a set of functionally relevant genes associated with the pathways of the hypothalamic-pituitary-gonadal (HPG; or HPG[L]-liver) axis of Japanese ricefish were examined after treatment with two model anti-estrogens, letrozole (LET) and tamoxifen (TAM), at three concentrations (30, 100 and 300μg/L) for 72h. The results showed that LET and TAM produced distinct expression profiles in a complex tissue- and gender-specific manner, confirming that they exert their anti-estrogenic effects via different molecular mechanisms. For example, the transcriptional levels of hepatic vitellogenin were significantly downregulated in females exposed to either LET or TAM, while they were significantly upregulated in TAM-exposed males and did not exhibit any change in LET-treated males. The expression of genes involved in steroidogenesis was also modulated by these two anti-estrogens in a way that corresponded with their anticipated mode of action. Overall, the data not only provide mechanistic information of anti-estrogenic chemicals but also demonstrate the potential of investigation of gene expression in the HPG(L) axis of model fish for diagnostic and predictive assessments of the risks associated with chemical exposure.
内分泌干扰物的研究越来越多地在基因的 mRNA 水平上进行，因为这种方法可能有助于深入了解作用模式和毒性机制。在这项研究中，研究了两种模型抗雌激素（来曲唑（LET）和他莫昔芬（TAM））在 72 小时内以三种浓度（30、100 和 300μg/L）处理后，与下丘脑-垂体-性腺（HPG；或 HPG[L]-肝脏）轴途径相关的一组功能相关基因的转录反应。结果表明，LET 和 TAM 以复杂的组织和性别特异性方式产生了不同的表达谱，证实它们通过不同的分子机制发挥抗雌激素作用。例如，暴露于 LET 或 TAM 的雌性肝脏卵黄蛋白原的转录水平显着下调，而暴露于 TAM 的雄性显着上调，而 LET 处理的雄性则没有变化。这两种抗雌激素还以与其预期作用模式相对应的方式调节了参与类固醇生成的基因的表达。总体而言，这些数据不仅提供了抗雌激素化学物质的机制信息，还证明了在模型鱼类的 HPG（L）轴中研究基因表达的潜力，可用于对与化学暴露相关的风险进行诊断和预测评估。
