Material Fumonisin Exposure and Pregnancy Outcome: Decoding the Sphingolipid Immu

描述(申请人提供)：伏马菌素B1(FB1)是一种在玉米中常见的真菌毒素，最近被发现与发育毒性有关。在主要依赖玉米作为主食的人群中，观察到母亲食用受FB1污染的玉米与神经管缺陷率增加之间的关联。FB1通过抑制神经酰胺合成酶来扰乱鞘磷脂的生物合成，导致狮身人面像碱基-1-磷酸和二酰甘油磷乙醇胺类脂的升高。所有这些化合物都是MHC样分子CD1d的候选配体，CD1d具有免疫监视和向自然杀伤T细胞(NKT)上不变的12 T细胞受体(NKT)递送脂质抗原的功能。激活的NKT细胞可以产生Th1或Th2细胞因子，这取决于配体的性质。暴露在FB1霉菌毒素下会引起免疫反应，包括Th1细胞因子(IFN3和TNF1)的产生。我们假设，暴露于FB1后积累的脂质化合物可被CD1d识别，并作为外源抗原呈现给NKT细胞，从而引发Th1细胞因子反应。妊娠期间Th1细胞因子的升高通常会导致流产，在所研究的大多数物种中，妊娠期间暴露于FB1会导致胎儿吸收的发生率增加。然而，在近交系的LM/BC小鼠品系中，怀孕母鼠暴露于FB1会导致高发生率的胎儿畸形。LM/BC小鼠先天免疫反应改变，子宫自然杀伤细胞(Unk)缺乏。CD1d定位于胎儿滋养层细胞，NKT和Unk定位于母胎界面的胎盘。受刺激的NKT细胞可以反式激活Unk产生Th1细胞因子。使用独特的近交系和突变小鼠模型，我们将检验以下假设：免疫活性动物暴露于FB1会导致CD1d-NKT Unk介导的Th1反应，导致滋养层细胞死亡和终止妊娠，而这一途径中的母体免疫缺陷允许妊娠继续足月，增加致畸原诱导的畸形的风险。这项建议的目的是确定导致孕妇暴露于FB1后胎儿畸形易感性增加的因素，并破译CD1d NKT细胞鞘脂-免疫系统在母胎界面上的相互作用，该相互作用在决定妊娠结局方面发挥关键作用。使用FB1作为模型致畸物质也将有助于我们理解母亲免疫缺陷在暴露于其他环境毒物后可能导致不良妊娠结局的机制。已有研究表明，NKT细胞缺陷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，拟议的研究有望为研究脂代谢、母体免疫和母胎界面Th1/Th2细胞因子谱变化在糖尿病胚胎病变中的作用开辟新的途径。与公共卫生相关：伏马菌素B1是一种真菌毒素，由玉米上常见的一种真菌产生，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，观察到母亲食用受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孕期暴露于伏马菌素后胎儿畸形的易感性中起作用。这项建议的目的是通过破译在决定妊娠结局中起关键作用的母胎界面上的鞘脂-免疫系统相互作用，来确定导致易感性增加的因素。

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.