Transplacental Chemoprevention of Lung Tumors and Lymphomas

我们的目标是加强以前发现的优势，消除劣势。重点仍然是开发与项目1和3相结合的经胎盘化学预防模式，以解决机制问题。我们研究了阻断机制和对母亲和胎儿的风险和益处，重点放在表观遗传学上，要求项目之间紧密整合。只有在其他项目和核心参与的情况下，才有可能扩大范围。中心假设是萝卜硫醚(SFN)和吲哚-3-甲醇(I3C)是化学预防药物，在PAH-经胎盘淋巴瘤、肺癌、肝癌和卵巢癌模型中，全食也是如此。机制是阻断和/或表观遗传，程度取决于植物化学物质。聚焦于相同的植物化学物质，增强整合性和协同性。我们通过追求3个综合目标来验证假设，从在怀孕小鼠身上的发现和机制研究进展到小型人体试验。通过使用人性化的鼠标，翻译性也得到了加强。这项在人类志愿者身上进行的试验利用了加速器质谱学(AMS)的非凡灵敏度。 具体目标1：测试人源化小鼠的反应；检查130种剂量反应并比较纯化的植物化学物质(在人类饮食水平)对全食的影响；测试母体膳食I3C和SFN暴露的窗口；测试启动后抑制；利用肺和肝脏特异性模型；确定Nrf2信号在基因剂量研究中的作用；以及测试F2代胎盘癌的化学预防。具体目标2：完全集中在表观遗传学与一个已知的目标(CYP1B1)，紧随其后的是p21，GSTP1和cyClind2，与项目1和3共同的有希望的目标。具体目标3：利用AMS来确定一种非致癌多环芳烃在人类中的药代动力学和I3C预处理的影响。评估I3C衍生物的生物利用度，并将I3C与整个食品(球芽甘蓝)进行比较。这是一个高度翻译的目标，作为进一步研究PAH暴露和经胎盘化学预防的前奏。这个项目与其他两个项目高度集成，因为我们将向两者提供组织，作为回报，我们将能够确定老鼠和人类之间化学预防机制的异同。

Our goal is to enhance strengths previously identified and eliminate weaknesses. The focus remains development of a transplacental chemoprevention model integrated with projects 1 & 3 to address mechanisms. We examine blocking mechanisms and risk VS benefit to mother and fetus with a focus on epigenetics demanding tight integration among projects. The scope is only possible with the participation of the other projects and cores. The central hypothesis is sulforaphane (SFN) and indole-3-carbinol (I3C) are chemopreventive agents, as are the whole foods, in a PAH-transplacental lymphoma, lung, liver and ovary cancer model. Mechanisms are blocking and/or epigenetic, the degree depending on the phytochemical. Focus on the same phytochemicals enhance integration and synergism. We test the hypotheses by pursuit of 3 integrated aims progressing from discovery and mechanistic studies in pregnant mice to a small human trial. The translational nature is also enhanced by use of a "humanized" mouse. The trial with human volunteers takes advantage of the remarkable sensitivity of accelerator mass spectromety (AMS). Specific Aim 1: Test the response of humanized mice; examine 130 dose-response and compare purified phytochemicals (at human dietary levels) to whole foods; test windows of maternal dietary I3C and SFN exposure; test post-initiation suppression; utilize lung- and liver-specific models; determine role of nrf2 signaling in a gene dosage study; and test transplacental cancer chemoprevention in an F2 generation. Specific aim 2: Focus entirely on epigenetics with a known target (CYP1B1), followed by p21, gstp1 and cyclind2, promising targets in common with projects 1 & 3. Specific aim 3: Utilize AMS to determine pharmacokinetics of a non-carcinogenic PAH in humans and impact of I3C pretreat. Assess bioavailability of I3C derivatives and compare I3C with the whole food (Brussels sprouts). This is a highly translational aim that serves as a prelude to further studies of PAH exposure and transplacental chemoprevention. This project is highly integrated with the other 2 as we will provide tissues to both and, in return, will be able to determine the similarities and differences of chemoprevention mechanisms between mouse and human.