Material Fumonisin Exposure and Pregnancy Outcome: Decoding the Sphingolipid Immu

描述（由申请人提供）：伏马菌素B1 （FB1）是一种常见于玉米的真菌毒素，最近与发育毒性有关。在主要以玉米为主食的人群中，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存在关联。FB1通过抑制神经酰胺合成酶破坏鞘脂的生物合成，导致鞘碱-1-磷酸酯和二酰基甘油磷酸乙醇胺脂质的升高。所有这些化合物都是mhc样分子CD1d的候选配体，CD1d在免疫监视和脂质抗原向自然杀伤t细胞（NKT）上不变的12 t细胞受体呈递中起作用。活化的NKT细胞可以产生Th1或Th2细胞因子库，这取决于配体的性质。暴露于FB1真菌毒素会引发涉及Th1细胞因子（IFN3和TNF1）产生的免疫反应。我们假设，FB1暴露后积累的脂质化合物被CD1d识别，并作为外源抗原呈递给NKT细胞，引发Th1细胞因子反应。妊娠期Th1细胞因子升高通常导致流产，在大多数被检查的物种中，妊娠期暴露于FB1会导致胎儿吸收发生率增加。然而，在近亲繁殖的LM/Bc小鼠品系中，妊娠鼠暴露于FB1会导致胎儿畸形的高发。LM/Bc小鼠先天免疫反应改变，子宫自然杀伤细胞（uNK）缺乏。CD1d在胎儿滋养细胞上发现，NKT和uNK在母胎界面的胎盘中发现。受刺激的NKT细胞可以反激活uNK产生Th1细胞因子。使用独特的近亲繁殖和突变小鼠模型，我们将验证FB1暴露在免疫能力强的动物中导致cd1 - nkt unk介导的Th1反应，导致滋养细胞死亡和妊娠终止，而母体在这一途径中的免疫缺陷使妊娠继续足月，增加了致畸物诱导畸形的风险。本研究的目的是确定母体FB1暴露后导致胎儿畸形易感性增加的因素，并解读母胎界面上CD1d NKT细胞鞘脂-免疫系统的相互作用，这种相互作用在决定妊娠结局中起关键作用。使用FB1作为模型致畸原也将有助于我们了解母体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。研究表明，NKT细胞缺陷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质代谢、母体免疫和母胎界面上Th1/Th2细胞因子谱的改变在糖尿病胚胎病中的作用开辟新的途径。公共卫生相关性：伏马菌素B1是一种真菌毒素，由一种在玉米上常见的真菌产生，最近被认为与发育毒性有关。在主要以玉米为主食的人群中，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存在关联。我们假设母体免疫缺陷在妊娠期暴露于伏马菌素后对胎儿畸形的易感性中起作用。本提案的目的是通过破译鞘脂-免疫系统在母胎界面的相互作用来确定增加易感性的因素，这在决定妊娠结局中起着关键作用。

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.