Tetrabromobisphenol A (TBBPA) as a modulator of tryptophan catabolism and maternal-fetal health

四溴双酚 A (TBBPA) 作为色氨酸分解代谢和母婴健康的调节剂

• 批准号: 9904631
• 负责人: Martha Susiarjo
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904631
• 关键词: Adoptive Transfer; Alleles; Allogenic; Amino Acids; Area; Biological Assay; Biological Response Modifiers; CD3 Antigens; Catabolism; Cells; Chemical Actions; Chemical Exposure; Chemicals; Conceptus; DNA Methylation; Data; Decidua; Development; Dioxygenases; Dose; Embryo; Endocrine Disruptors; Environmental Exposure; Environmental Health; Environmental Risk Factor; Enzymes; Event; Exposure to; FOXP3 gene; Failure; Female; Fetal Resorption; Fetal health; Fetus; Flow Cytometry; Gene Expression; Genes; Genetic; Genomic Imprinting; Goals; Human; IL2RA gene; Immune Tolerance; Immune response; Immunity; Immunologics; Immunology; Intervention; Kynurenine; Laboratories; Link; Maternal Health; Maternal-Fetal Exchange; Measures; Mediating; Molecular; Mothers; Mus; Outcome; Partner in relationship; Pathologic; Pilot Projects; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Maintenance; Pregnancy Outcome; Pregnancy Rate; Pregnancy loss; Pregnant Women; Premature Labor; Process; Regulation; Regulatory T-Lymphocyte; Reproductive Health; Research; Role; Spontaneous abortion; T cell differentiation; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tryptophan; Uterus; Work; adverse pregnancy outcome; base; bisulfite sequencing; chromatin immunoprecipitation; epigenetic regulation; fetal; fetal loss; histone modification; immune function; immunoregulation; imprint; indoleamine; insight; liquid chromatography mass spectrometry; mRNA Expression; man; mouse model; novel; offspring; pregnant; prenatal exposure; protein expression; tetrabromobisphenol A; therapy design

ABSTRACT Accumulating evidence has demonstrated that exposure to man-made chemicals disrupts human reproductive health. Elucidation of the relevant mechanisms is critical for designing intervention strategies. The goal of the proposed work is to investigate the role of endocrine disrupting chemicals (EDCs) in modulating tryptophan catabolism as a novel mechanism of environmental exposure-induced adverse pregnancy outcomes. Tryptophan catabolism is a regulator of maternal immune tolerance during pregnancy. Failure to degrade tryptophan in the pregnant mother is linked to a significant proportion of human miscarriages, preeclampsia, and premature labor. A key event of this process is activation of the placental Ido1 gene that encodes for a major tryptophan-degrading enzyme. Our laboratory has shown that in utero exposure to a representative EDC, tetrabromobisphenol A (TBBPA), reduces placental Ido1 gene and protein expression, and is linked to increased rates of fetal resorption. In this proposal, we wish to investigate whether exposure to TBBPA alters pregnancy outcomes by perturbing tryptophan catabolism and reducing maternal-fetal immune tolerance. We will expose female mice to environmentally relevant doses of TBBPA (i.e., 5, 50, and 500 µg/kg bw/day) prior to mating, during mating, and throughout pregnancy, and analyze the pregnant mice and conceptuses. We wish to determine if exposures are linked to reduced maternal immunity by analyzing a subset of immunosuppressive T cells called “regulatory T cells” or “Tregs”. Using flow cytometry, we will determine Treg number in the decidua and uterus of controls and exposed pregnant mice. Increased tryptophan catabolism during pregnancy has been linked to expansion of maternal Tregs. As elevated maternal Tregs favor pregnancy maintenance, we anticipate that TBBPA-exposed mice have reduced Tregs. To determine if increased rate of fetal loss in TBBPA-exposed pregnant mice is causatively linked to reduced maternal Treg number, we will perform an adoptive transfer study using Tregs from donor Foxp3-GFP mice. Additionally, we will perform liquid chromatography and mass spectrometry-based assays to measure levels of tryptophan and its catabolites in the pregnant dam, fetus, and placenta during sequential stages of pregnancy. We wish to elucidate whether TBBPA-induced effects on maternal immunity and pregnancy outcomes are linked to abnormal levels of tryptophan catabolites. Finally, our preliminary studies show that the Ido1 gene is subject to genomic imprinting. We will investigate effects of TBBPA exposure on imprinting regulation of the Ido1 locus by analyzing allele-specific gene expression, DNA methylation and/or posttranslational histone modifications through quantitative real time PCR, bisulfite sequencing, and chromatin immunoprecipitation.

抽象的 越来越多的证据表明，接触人造化学物质会扰乱人类生殖 阐明相关机制对于设计干预策略至关重要。 拟议的工作是研究内分泌干扰化学物质（EDC）在调节色氨酸中的作用 分解代谢是环境暴露引起不良妊娠结局的一种新机制。 色氨酸分解代谢是妊娠期间母体免疫耐受的调节剂。 怀孕母亲体内的色氨酸与很大一部分人类流产、先兆子痫、 这个过程的一个关键事件是胎盘 Ido1 基因的激活，该基因编码 我们的实验室已经证明，在子宫内接触有代表性的色氨酸降解酶。 EDC，四溴双酚 A (TBBPA)，可降低胎盘 Ido1 基因和蛋白质表达，并与 在本提案中，我们希望研究接触 TBBPA 是否会改变。 我们通过扰乱色氨酸分解代谢和降低母胎免疫耐受来改善妊娠结果。 事先将雌性小鼠暴露于环境相关剂量的 TBBPA（即 5、50 和 500 µg/kg 体重/天） 到交配、交配期间和整个怀孕期间，并分析怀孕小鼠和受孕情况。 希望通过分析一部分来确定暴露是否与母体免疫力下降有关 免疫抑制性 T 细胞称为“调节性 T 细胞”或“Treg”，我们将使用流式细胞术测定 Treg。 对照组和暴露的怀孕小鼠的蜕膜和子宫中的色氨酸分解代谢增加。 怀孕期间与母体 Tregs 的扩张有关，因为母体 Tregs 的升高受到青睐。 妊娠维持后，我们预计暴露于 TBBPA 的小鼠会减少 Tregs 以确定是否会减少。 暴露于 TBBPA 的怀孕小鼠胎儿丢失率增加与母体 Treg 减少有关 编号，我们将使用来自供体 Foxp3-GFP 小鼠的 Tregs 进行过继转移研究。 将进行基于液相色谱和质谱的测定来测量色氨酸和 我们希望在怀孕的连续阶段中，其在怀孕母体、胎儿和胎盘中的分解代谢物。 阐明 TBBPA 对母体免疫力和妊娠结局的影响是否与 最后，我们的初步研究表明 Ido1 基因受到影响。 我们将通过以下方法研究 TBBPA 暴露对 Ido1 基因座印记调控的影响。 分析等位基因特异性基因表达、DNA 甲基化和/或翻译后组蛋白修饰 通过实时定量 PCR、亚硫酸氢盐测序和染色质免疫沉淀。