Transplacental Chemoprevention of Lung Tumors and Lymphomas

我们的目标是增强先前确定的优势，消除弱点。重点仍然是开发经胎盘化学预防模型，与项目1和项目3相结合，以解决机制问题。我们研究了阻断机制和风险VS对母亲和胎儿的好处，重点是表观遗传学，需要在项目之间紧密整合。这个范围只有在其他项目和核心的参与下才有可能实现。中心假设是萝卜硫素（SFN）和吲哚-3-甲醇（I3C）是化学预防剂，就像全食物一样，在多环芳烃经胎盘淋巴瘤、肺癌、肝癌和卵巢癌模型中。机制有阻断和/或表观遗传，程度取决于植物化学。专注于同一种植物化学物质可以增强整合和协同作用。我们通过追求从怀孕小鼠的发现和机制研究到小型人体试验的3个综合目标来验证这些假设。通过使用“人源化”老鼠，翻译性质也得到了增强。人类志愿者的试验利用了加速器质谱（AMS）非凡的灵敏度。

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.