Mycotoxins and Birth Defects: A Global Health Concern?

描述(申请人提供)：伏马菌素B1(FB1)是一种由玉米中一种常见真菌污染产生的真菌毒素。在以玉米为主食的全球社区中，怀孕早期摄入受FB1污染的食物最近被认为与患有神经管缺陷(NTDS)的后代的风险增加有关。FB1干扰神经鞘糖脂的生物合成，但导致异常形态发生的确切生化变化尚不清楚。该研究计划的目标是确定预测FB1暴露与胎儿畸形风险增加相关的生化和遗传生物标记物。在危地马拉，玉米中出现FB1的情况是有据可查的，NTDS的发病率往往是这种类型出生缺陷全球平均水平的6-10倍。已经进行了初步暴露评估，并确定了玉米中FB1含量经常较高的特定社区。这项拟议的研究将使用从小鼠研究中获得的信息来评估和验证从已知食用大量受FB1污染的玉米的妇女那里收集的人类样本中的生物标志物。该项目涉及克雷顿大学、杜克大学、USDA-ARS和危地马拉CIENSA的研究人员之间的合作努力。危地马拉的妇女将被要求完成旨在识别玉米高消费者和低消费者的问卷，登记的受试者将提供尿点和血点以供进一步分析。将在小鼠身上进行平行暴露研究，以确定FB1诱导血液中鞘脂代谢物变化的剂量反应阈值。小鼠模型也将被用来识别母亲血液和胚胎神经组织中与NTDS风险增加相对应的特定鞘糖脂代谢物，这些生物标记物将在从暴露于高水平和低水平FB1的玉米消费者那里获得的人血斑点中进行评估。此外，小鼠模型将被用来进一步研究导致神经管关闭失败的潜在信号机制。其他研究将集中在发现和验证神经鞘脂途径基因中预测易感性增加的基因表达谱和基因突变。将根据对小鼠鞘脂基因表达谱的qPCR分析，选择用于在人类样本中进行分析的候选基因。神经鞘脂代谢和信号通路中的基因将被筛选出人类血点和敏感与耐药小鼠品系的血点的突变。拟议研究的信息将成为前瞻性和回溯性流行病学研究的基础，以确定玉米培养物中患有非传染性疾病的高危妇女。此外，基于机制的生物标志物将为风险评估提供一个关键的、目前缺乏的研究工具，并有助于制定战略，在经常消费受FB1污染的玉米的全球社区减少NTDS的发生率。 与公共卫生相关：伏马菌素(FB1)是一种由玉米的一种常见真菌污染物产生的真菌毒素。最近观察到，在怀孕早期摄入受FB1污染的玉米与生下患有神经管缺陷(NTD)的孩子的风险增加之间存在关联。该应用程序的目的是识别尿液中暴露于FB1的生物标记物，以及血液斑点中与增加胎儿畸形风险唯一相关的生化和遗传生物标记物。FB1接触数据、尿液和血斑将从危地马拉的玉米消费者中收集。在对FB1诱导的NTDS敏感或耐药的小鼠模型中进行的机制研究将能够识别鞘磷脂代谢物、基因表达谱和增加风险的基因突变。其目标是发现和验证可用于预测人类风险的生物标记物，以便我们能够预防和/或减少严重依赖玉米作为主食的全球人口中NTDS的发生率。

DESCRIPTION (provided by applicant): Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of corn. Ingestion of FB1-contaminated food during early pregnancy has recently been linked to increased risk for offspring with neural tube defects (NTDs) in global communities that rely on maize as a dietary staple. FB1 interferes with de novo sphingolipid biosynthesis, but the exact biochemical changes that contribute to abnormal morphogenesis are unknown. The objectives of the research plan are to identify biochemical and genetic biomarkers that predict FB1 exposures associated with increased risk for fetal malformations. In Guatemala, the occurrence of FB1 in maize is well documented, and the incidence of NTDs is often 6-10 times the global average for this type of birth defect. Preliminary exposure assessments have been conducted, and specific communities have been identified where FB1 in maize is frequently high. The proposed research will use information obtained from mouse studies to assess and validate biomarkers in human samples collected from women known to consume large amounts of FB1-contaminated maize. The project involves a collaborative effort between investigators at Creighton University, Duke University, USDA-ARS and CIENSA in Guatemala. Women in Guatemala will be asked to complete questionnaires intended to identify high and low consumers of maize, and enrolled subjects will provide urine and blood spots for further analysis. Parallel exposure studies will be done in mice in order to determine the dose-response threshold for FB1-induced alterations in sphingolipid metabolites in blood. Mouse models will also be used to identify the specific sphingolipid metabolites in maternal blood and embryonic neural tissue that correspond to increased risk for NTDs, and these biomarkers will be evaluated in human blood spots obtained from maize consumers exposed to high and low levels of FB1. In addition, mouse models will be used to further investigate the underlying signaling mechanisms involved that result in failure of neural tube closure. Additional studies will focus on the discovery and validation of gene expression profiles and genetic mutations in sphingolipid pathway genes that predict increased susceptibility. Candidate genes for analysis in human samples will be selected based on qPCR analyses of sphingolipid gene expression profiles in mice. Genes in sphingolipid metabolism and signaling pathways will be screened for mutations in human blood spots and in blood spots from susceptible vs. resistant mouse strains. Information from the proposed studies will form the basis for prospective and retrospective epidemiological studies to identify women at high risk for NTDs in maize-based cultures. In addition, mechanism-based biomarkers will provide a critical, and currently lacking, research tool for risk assessment, and aid in developing strategies for reducing the incidence of NTDs in global communities where consumption of FB1-contaminated maize is frequent. PUBLIC HEALTH RELEVANCE: Fumonisin (FB1) is a mycotoxin produced by a common fungal contaminant of maize. An association has recently been observed between ingestion of FB1-contaminated maize during early pregnancy and increased risk for having a child with a neural tube defect (NTD). The purpose of the application is to identify biomarkers of FB1 exposure in urine, and biochemical and genetic biomarkers in blood spots that are uniquely linked to increased risk for fetal malformations. FB1 exposure data, urine, and blood spots will be collected from human subjects in Guatemala who are consumers of maize. Mechanistic studies in mouse models that are susceptible or resistant to FB1-induced NTDs will enable the identification of sphingolipid metabolites, gene expression profiles, and genetic mutations that confer increased risk. The goal is the discovery and validation of biomarkers that can be used to predict risk in humans, such that we can prevent and/or reduce the incidence of NTDs in global populations that rely heavily on maize as a dietary staple.