Biological impact of xenobiotics in the female reproductive tract

环境污染物抵抗生物降解，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导致接触二恶英的母亲的后代甚至后代的长期生殖障碍。这些遗传性生殖功能障碍背后的分子机制尚不完全清楚。这项拟议的研究将使用独特的细胞模型和转基因小鼠来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受雌激素和孕激素影响的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了分泌和吸收功能所必需的分子机制。利用二恶英反应的小鼠模型，我们将确定在出生前和出生后发育期间接触二恶英的最敏感时间窗口。我们将使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出生前接触二恶英后染色体外DNA序列和microRNA模式的变化。我们的长期目标是确定可能导致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.