Material Fumonisin Exposure and Pregnancy Outcome: Decoding the Sphingolipid Immu

材料伏马菌素暴露和妊娠结果：解码鞘脂免疫

• 批准号: 7646413
• 负责人: JANEE GELINEAU-VAN WAES
• 金额: $ 9.56万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-08-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7646413
• 关键词: Affect; Anabolism; Animals; Antigens; Autoimmune Diseases; Binding; Biochemical Genetics; Candidate Disease Gene; Cell Death; Cells; Child; Code; Collaborations; Complex; Congenital Abnormality; Consumption; Coupled; Data; Development; Diabetes Mellitus; Diabetic mother; Ensure; Enzymes; Epidemiologist; Evaluation; Excision; Exhibits; Experimental Animal Model; Exposure to; Face; Fetal Development; Fetal Resorption; Fetal Tissues; Fetus; Flow Cytometry; Food; Fumonisin B1; Fumonisins; Gene Expression; Gene Proteins; Gene Silencing; Genes; Goals; Guatemala; Health; Health Professional; Human; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunologic Deficiency Syndromes; Immunologic Surveillance; Immunology; Immunophenotyping; Incidence; Individual; Infectious Agent; Interdisciplinary Study; Investigation; Knowledge; Label; Ligands; Link; Lipids; Maternal Exposure; Maternal-Fetal Exchange; Mediating; Metabolism; Modeling; Morphology; Mouse Strains; Mus; Mutation; Mycotoxins; Natural Killer Cells; Nature; Neural Tube Defects; Obesity; Outcome; Pathology; Pathway interactions; Perinatal Exposure; Phenotype; Phospholipid Interaction; Phospholipid Metabolism; Phospholipids; Placenta; Play; Population; Populations at Risk; Predisposition; Pregnancy; Pregnancy Outcome; Prevention; Production; Relative (related person); Research; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Rural Population; SWV Mouse; Screening procedure; Secondary to; Sphingolipids; T-Cell Receptor; Technology; Teratogens; Teratology; Termination of pregnancy; Testing; Toxic Environmental Substances; Toxic effect; Toxicology; Toxin; Transactivation; Transgenic Mice; Translational Research; Universities; abortion; base; carcinogenicity; cell mediated immune response; cytokine; design; diabetic embryopathy; dihydroceramide desaturase; embryo tissue; embryo/fetus antigen; fetal; fungus; high risk; immune function; inorganic phosphate; insight; killer T cell; lipid metabolism; malformation; mouse model; mutant mouse model; offspring; phosphoethanolamine; pregnant; prevent; protein expression; public health relevance; research study; response; sphinganine; trophoblast

DESCRIPTION (provided by applicant): Fumonisin B1 (FB1) is a mycotoxin commonly found on corn that has recently been implicated in developmental toxicity. An association between maternal consumption of FB1-contaminated corn and increased neural tube defect rates has been observed in human populations relying primarily on corn as their dietary staple. FB1 disrupts sphingolipid biosynthesis by inhibiting ceramide synthase, resulting in elevations in sphingoid base-1-phophates, and diacylglycerolphosphoethanolamine lipids. All of these compounds are candidate ligands for the MHC-like molecule CD1d that functions in immune surveillance and the presentation of lipid antigens to the invariant 12 T-cell receptor on natural killer T-cells (NKT). Activated NKT cells can produce either a Th1 or a Th2 cytokine repertoire, depending on the nature of the ligand. Exposure to the FB1 mycotoxin elicits an immune response that involves the production of Th1 cytokines (IFN3 and TNF1). We hypothesize that the lipid compounds that accumulate after FB1 exposure are recognized by CD1d and presented to NKT cells as foreign antigens that elicit a Th1 cytokine response. Elevated Th1 cytokines during pregnancy often result in abortion, and in most species examined, gestational exposure to FB1 results in an increased incidence of fetal resorptions. However, in the inbred LM/Bc mouse strain, exposure of pregnant dams to FB1 results in a high incidence of fetal malformations. The LM/Bc mouse has an altered innate immune response, and deficiencies in uterine natural killer cells (uNK). CD1d is found on fetal trophoblast cells, and NKT and uNK are found in the placenta at the maternal-fetal interface. Stimulated NKT cells can transactivate uNK to produce Th1 cytokines. Using unique inbred and mutant mouse models, we will test the hypothesis that FB1 exposure in immunocompetent animals results in a CD1d-NKT uNK-mediated Th1 response that results in trophoblast cell death and pregnancy termination, while maternal immunodeficiencies in this pathway allow the pregnancy to continue to term, increasing the risk for teratogen-induced malformations. The objectives of this proposal are to determine the factors that confer increased susceptibility to fetal malformations following maternal FB1 exposure, and decipher the CD1d NKT cell sphingolipid- immune system interactions at the maternal-fetal interface that play a critical role in determining pregnancy outcome. The use of FB1 as a model teratogen will also facilitate our understanding of the mechanisms through which maternal immunodeficiencies may contribute to adverse pregnancy outcomes following exposure to other environmental toxicants. It has been shown that NKT cell deficiencies result in autoimmune disorders such as diabetes, and that the offspring of diabetic mothers are at increased risk for fetal malformations. The proposed studies are therefore expected to open new avenues for investigating the role of alterations in lipid metabolism, maternal immunity, and Th1/Th2 cytokine profiles at the maternal-fetal interface as contributing factors in diabetic embryopathies. PUBLIC HEALTH RELEVANCE: Fumonisin B1 is a mycotoxin produced by a fungus commonly found on corn that has recently been implicated in developmental toxicity. An association between maternal consumption of fumonisin-contaminated corn and increased risk for offspring with birth defects has been observed in human populations relying primarily on corn as their dietary staple. We hypothesize that maternal immunodeficiencies play a role in susceptibility to fetal malformations following gestational exposure to fumonisin. The objectives of this proposal are to determine the factors that contribute to increased susceptibility by deciphering the sphingolipid-immune system interactions at the maternal-fetal interface that play a critical role in determining pregnancy outcome.

性状（由申请方提供）：伏马菌素B1（FB 1）是一种常见于玉米中的真菌毒素，最近发现与发育毒性有关。在主要依赖玉米作为主食的人群中，观察到母亲食用FB 1污染玉米与神经管缺陷率增加之间的关联。FB 1通过抑制神经酰胺合成酶破坏鞘脂的生物合成，导致鞘氨醇碱-1-磷酸盐和二酰基甘油磷酸乙醇胺脂质升高。所有这些化合物都是MHC样分子CD 1d的候选配体，CD 1d在免疫监视和将脂质抗原呈递给自然杀伤T细胞（NKT）上的不变12 T细胞受体中发挥作用。活化的NKT细胞可以产生Th 1或Th 2细胞因子库，这取决于配体的性质。暴露于FB 1真菌毒素会引发涉及Th 1细胞因子（IFN 3和TNF 1）产生的免疫反应。我们假设FB 1暴露后积累的脂质化合物被CD 1d识别，并作为引起Th 1细胞因子应答的外源抗原呈递给NKT细胞。妊娠期间Th 1细胞因子升高通常导致流产，在大多数检查的物种中，妊娠期暴露于FB 1导致胎儿吸收发生率增加。然而，在近交系LM/Bc小鼠品系中，妊娠母鼠暴露于FB 1导致胎儿畸形的高发生率。LM/Bc小鼠具有改变的先天性免疫应答和子宫自然杀伤细胞（uNK）的缺陷。CD 1d存在于胎儿滋养层细胞上，NKT和uNK存在于母胎界面的胎盘中。刺激的NKT细胞可以反式激活uNK产生Th 1细胞因子。使用独特的近交系和突变小鼠模型，我们将测试的假设，FB 1暴露在免疫功能正常的动物的结果在CD 1d-NKT uNK介导的Th 1反应，导致滋养层细胞死亡和妊娠终止，而在这一途径的母体免疫缺陷允许怀孕继续长期，增加致畸剂诱导的畸形的风险。本提案的目的是确定母体暴露于FB 1后导致胎儿畸形易感性增加的因素，并破译在确定妊娠结局中起关键作用的母胎界面处的CD 1d NKT细胞鞘脂-免疫系统相互作用。使用FB 1作为模型致畸剂也将有助于我们了解母体免疫缺陷可能导致不良妊娠结局暴露于其他环境毒物后的机制。研究表明，NKT细胞缺乏会导致自身免疫性疾病，如糖尿病，糖尿病母亲的后代患胎儿畸形的风险增加。因此，拟议的研究有望开辟新的途径，调查的作用，改变脂质代谢，母体免疫，和Th 1/Th 2细胞因子在母胎界面的糖尿病胚胎病的影响因素。公共卫生关系：伏马菌素B1是一种真菌毒素，由玉米上常见的真菌产生，最近被认为与发育毒性有关。在主要依赖玉米作为主食的人群中，观察到母亲食用伏马菌素污染的玉米与后代出生缺陷风险增加之间的关联。我们假设母体免疫缺陷在妊娠期暴露于伏马菌素后胎儿畸形的易感性中起作用。本提案的目的是通过解读母胎界面的鞘脂-免疫系统相互作用（在确定妊娠结局中起关键作用），确定导致易感性增加的因素。