双酚A影响稀有鮈鲫卵巢发育的生态毒理基因组学研究

Bisphenol A (BPA) has wide industrial applications and was testified to be an endocrine disrupting chemical. Its reproductive toxicity has been paid increasing attentions. Based on our previous findings, the present study will investigate the impacts of low-dose and high-dose BPA on the ovarian development in rare minnow Gobiocypris rarus, which was confirmed to be sensitive to BPA, by histological analysis of ovarian development, sex steroids assay, vitellogenin measurement, the genomic methods of high-through RNA sequencing technology and real-time PCR analysis. The findings of present study will elucidate the toxicological pathways of inhibiting effects on ovarian development for low-dose BPA, explore the effects of high-dose BPA on the ovarian development and its molecular mechanisms, provide sensitive molecular biomarkers for BPA early warning, and explore the molecular mechanism of nonmonotonic effects in BPA exposure. The present study will facilitate exact ecological risk assessments of BPA, provide a whole characteristic gene expression profile in rare minnow for BPA exposure, increase the certainty for BPA ecological risk assessments, and produce high-through gene sequence data which would be significant to extend ecotoxicogenomics studies in rare minnow.

双酚A(BPA)是一种广泛应用化学品，但是它具有内分泌干扰作用，目前它的生殖毒性备受关注，本项目在预实验的基础上使用对BPA反应敏感的稀有鮈鲫为实验动物，通过分析卵巢的发育状况，检测性类固醇激素和卵黄蛋白原水平，用转录组测序和实时定量PCR的基因组学技术，研究低剂量和高剂量BPA对卵巢发育的影响，阐明低剂量BPA抑制卵巢发育的毒理途径,探索高剂量BPA对卵巢发育的影响及其分子机制，获得BPA早期预警的敏感分子生物标志物，探索 BPA非单调剂量效应的分子机制。本项目的研究成果将有助于对BPA进行正确的生态风险评价，也有助于获得稀有鮈鲫在BPA毒性作用下的特征性整体表达图谱，增加BPA生态风险评价的确定性，获得稀有鮈鲫大量的基因组序列，为其生态毒理基因组学的广泛应用奠定基础。

BPA的生殖毒性目前受到广泛关注，本研究以稀有鮈鲫为实验动物，研究了BPA对鱼类的卵巢发育、类固醇激素、甘油三酯、氧化应激等影响，研究了BPA暴露对性腺组织类固醇激素合成、激素受体、转录调控因子、性腺发育、脑-垂体-性腺轴等相关基因的mRNA表达影响，进行了BPA暴露对性腺转录组影响的研究，对转录组中受到较大影响的代谢通路如脂肪代谢、免疫信号通路TLR4/NF-κB及外源及內源物质生物转化中PXR通路进行了进一步验证和分析，获得如下主要结果：BPA对性腺类固醇激素合成相关基因的表达有重要影响，BPA对性腺类固醇激素合成基因的干扰可能通过类固醇激素受体、转录调控因子和促性腺激素受体发挥作用，BPA对性腺功能的干扰能够通过脑-垂体-性腺轴负反馈调节上游的GnRH系统，BPA处理后，类固醇激素的作用、Vtg和甘油三酯的积累、氧化胁迫所诱导的蛋白水解都可能造成卵巢重量的改变，最终影响卵细胞的成熟，本项目阐明了鱼类卵巢组织的BPA非单调剂量效应的分子机制，本研究所获得转录组数据将为鱼类生态毒理研究提供数据支持。