Sulforaphane-mediated epigenetic modulation of ethanol-induced apoptosis and teratogenesis

产前接触酒精是导致智力低下的主要已知原因。越来越多的证据表明 细胞过度死亡是酒精性出生缺陷发病机制的重要组成部分。然而， 在理解乙醇是如何导致胚胎细胞凋亡的过程中，存在一个根本的空白。 萝卜硫素(SFN)是一种在西兰花芽中含量丰富的化学物质。令人信服的证据表明，SFN 或者富含SFN的西兰花芽通过激活Nrf2信号来触发抗氧化酶的诱导 并预防癌症和其他疾病。最近发现SFN可以调节基因的表达 通过表观遗传机制。我们最近证明，SFN可以显著减少乙醇- 诱导神经脊细胞(NCCs)凋亡。我们的长期目标是发展 防止酒精致畸的有效策略；预防酒精致畸的策略 通过靶向参与细胞凋亡的特定途径来实现细胞凋亡。本次特别会议的总体目标是 建议阐明SFN在表观遗传上调节抗细胞凋亡的机制 基因表达和防止乙醇诱导的细胞凋亡，并开发一种安全有效的治疗方案 使用SFN，一种安全的“营养食品”，降低FASD的发生率和严重程度。这一点的中心假设是 项目是乙醇诱导的表观遗传改变导致抗凋亡基因的异常表达， 导致胚胎过度凋亡和畸形，这可以通过表观遗传来防止 SFN或富含SFN的西兰花芽提取物诱导的调制。我们的假设是建立在 我们实验室提供了强大的初步数据基础。为了验证我们的假设，有以下几个具体目标 将致力于：目标1：确定在表观遗传上被乙醇和 在乙醇暴露的NCCs和小鼠胚胎中被SNF去抑制。目标2：通过以下方式阐明其作用机制 其中SFN在表观遗传上调控抗凋亡基因的表达和乙醇中的细胞凋亡- 暴露的NCC和小鼠胚胎。目的3：验证表观遗传调控抗肿瘤基因的假设。 母体膳食富含SFN的西兰花芽提取物(BSE)的凋亡基因代表了一种新的治疗方法 预防酒精致畸的策略。拟议的工作具有创新性，因为它侧重于 一种防止乙醇诱导的新方法--抗细胞凋亡基因的表观遗传调控 畸形症。申请中描述的理论概念也具有很高的创新性，因为这是 第一项试图通过使用从蔬菜中提取的生物活性化合物来预防FASD的研究。这个 这项研究的结果将是重要的，因为它们有望说明一种实用的 FASD的营养治疗策略。

Prenatal ethanol exposure is the leading known cause of mental retardation. Growing evidence suggests that excessive cell death is a major component of the pathogenesis of ethanol-induced birth defects. However, there is a fundamental gap in understanding how ethanol leads to apoptotic cell death in embryos. Sulforaphane (SFN) is a chemical that is abundant in broccoli sprouts. Compelling evidence indicates that SFN or SFN-rich broccoli sprouts trigger the induction of antioxidant enzymes through activation of Nrf2 signaling and prevent cancer and other diseases. It was recently discovered that SFN can regulate gene expression through epigenetic mechanisms. We have recently demonstrated that SFN can significantly diminish ethanol- induced apoptosis in neural crest cells (NCCs). Our long-term goal is directed toward the development of effective strategies against ethanol's teratogenesis; strategies based on prevention of ethanol-induced apoptosis through targeting specific pathways involved in apoptosis. The overall objective of this particular proposal is to elucidate the epigenetic mechanisms by which SFN epigenetically regulates the anti-apoptotic gene expression and prevent ethanol-induced apoptosis, and to develop a safe and effective regimen to diminish the incidence and severity of FASD using SFN, a safe “nutraceutical”. The central hypothesis of this project is that ethanol-induced epigenetic alterations lead to aberrant expression of the anti-apoptotic genes, resulting in excessive apoptosis and malformations in embryos, which can be prevented by epigenetic modulation elicited by SFN or SFN-rich broccoli sprout extract. Our hypothesis has been formulated on the basis of strong preliminary data produced in our laboratory. To test our hypothesis, the following specific aims will be addressed: Aim 1: To identify the anti-apoptotic genes that are epigenetically silenced by ethanol and derepressed by SNF in ethanol-exposed NCCs and mouse embryos. Aim 2: To elucidate the mechanisms by which SFN epigenetically modulates the expression of the anti-apoptotic genes and apoptosis in ethanol- exposed NCCs and mouse embryos. Aim 3: To test the hypothesis that epigenetic modulation of the anti- apoptotic genes by maternal dietary SFN-rich broccoli sprout extract (BSE) represents a novel therapeutic strategy for preventing ethanol-induced teratogenesis. The proposed work is innovative, because it focuses on a novel approach, epigenetic modulation of the anti-apoptotic genes, to preventing ethanol-induced teratogenesis. The theoretical concept described in the application is also highly innovative because this is the first study attempting to prevent FASD through the use of bioactive compounds derived from a vegetable. The results from this study will be significant, because they are expected to illustrate the potential of a practical nutraceutical-based therapeutic strategy for FASD.