Biological impact of xenobiotics in the female reproductive tract

环境污染物具有抗生物降解性，在食物链中积累，影响各种生物功能。二恶英类化学物质会干扰类固醇激素的作用，损害生殖功能。越来越多的证据表明，产前接触二恶英类环境化学品会对接触二恶英的母亲的后代甚至后代造成长期的生殖障碍。这些遗传生殖功能障碍的分子机制尚不完全清楚。本研究将利用独特的细胞模型和转基因小鼠研究这些化学物质诱导的分子机制。利用雌性生殖器官的永生化细胞，我们将研究这些化学物质对雌激素和黄体酮影响下上皮细胞功能分化的影响。我们假设二恶英类化学物质干扰分泌和吸收功能所必需的分子机制。使用二恶英反应小鼠模型，我们将确定在产前和产后发育期间二恶英暴露的最敏感时间窗。我们将采用现代荧光成像技术和新的高灵敏度检测和分析技术来研究产前暴露于二恶英后染色体外DNA序列和microRNA模式的变化。我们的长期目标是确定可能赋予遗传性功能性生殖障碍的基因组动力学机制。

Environmental pollutants are resistant to biodegradation, accumulate in the food chain and affect various biological functions. Dioxin-type chemicals interfere with steroid hormone action and impair reproductive functions. There is increasing evidence that prenatal exposure to dioxin-type environmental chemicals results in long-term reproductive disturbances in the offspring of exposed mothers and even in further generations. The molecular mechanisms underlying these heritable reproductive dysfunctions are not fully understood. The proposed research will investigate the molecular mechanisms induced by these chemicals using unique cell models and transgenic mice. Utilizing immortalized cells of female reproductive organs we will study the impact of these chemicals on the functional differentiation of epithelial cells which is regulated under the influence of estrogen and progesterone. We hypothesize that dioxin-type chemicals interfere with molecular mechanisms essential for secretory and resorptive functions. Using dioxin-responsive mouse models we will determine the most sensitive time windows for dioxin exposure during pre- and post-natal development. We will employ modern fluorescence imaging techniques and novel highly sensitive detection and analysis techniques to investigate extra-chromosomal DNA sequences and alterations in microRNA patterns following pre-natal exposure to dioxin. Our long-term goal is to identify the mechanisms of genome dynamics which may confer heritable functional reproductive disorders.