Toxicant Exposure Impacts Host-pathogen interactions within the Reproductive Tract

有毒物质暴露影响生殖道内宿主与病原体的相互作用

• 批准号: 10359096
• 负责人: Jennifer A Gaddy
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359096
• 关键词: Address; Affect; Afghanistan; Age; Anti-Bacterial Agents; Area; Bacteremia; Bacteria; Basic Science; Biological Response Modifiers; Birth; Cause of Death; Cells; Cellular biology; Child; Conflict (Psychology); DNA; Data; Developmental Process; Diagnostic; Dioxins; Disease Outcome; Disease Progression; Endocrine Disruptors; Environment; Environmental Pollution; Exposure to; Female; Fertility; Fiber; Fire - disasters; Generations; Gravid; Growth; Homeostasis; Human; Immobilization; Immune; Immune System Diseases; Immune response; Immune system; Immunologics; Impairment; Infection; Inflammation; Inflammatory; Intervention; Iraq; Knowledge; Lead; Link; Maintenance; Maternal-Fetal Exchange; Matrix Metalloproteinases; Membrane; Military Personnel; Modeling; Molecular; Mothers; NADPH Oxidase; Natural Immunity; Oils; Outcome; Peptides; Play; Population; Predisposition; Pregnancy; Premature Birth; Prevention approach; Production; Publishing; Reactive Oxygen Species; Recording of previous events; Reporting; Reproductive Health; Reproductive Process; Reproductive Tract Infections; Research Proposals; Risk; Role; Streptococcal Infections; Streptococcus Group B; Tetrachlorodibenzodioxin; Tissues; Toxic Environmental Substances; Toxicant exposure; Translational Research; Veterans; Vietnam; Woman; adverse pregnancy outcome; agent orange; antimicrobial; burn pit; carcinogenesis; combustion product; environmental stressor; extracellular; female fertility; fetal; host microbiota; immune system function; improved; improved outcome; in utero; intraamniotic infection; macrophage; male; male fertility; mouse model; neonatal sepsis; novel strategies; organ on a chip; pathogen; pre-clinical; pregnant; programs; reproductive; reproductive outcome; reproductive tract; response; toxicant

Project Summary Exposure to persistent environmental toxicants (such as dioxin) is a global problem, but disproportionately affects Veterans who were exposed dioxin derived from burn pits or Agent Orange. Dioxin exposure has been linked to diminished fertility and an increased risk of preterm birth in both males and females, even when the exposure occurred in utero. Recent studies indicate that female Veterans have increased risk of preterm birth associated with recent deployment, underscoring the need for better diagnostics and interventions to eliminate the risk of preterm birth associated with the unique environmental stressors encountered by Veterans. However, little is known about the underlying molecular factors that contribute to this risk. We hypothesize that exposure to environmental toxicants leads to perturbations in the host immune system programme which lead to increased susceptibility to inflammatory insults (such as infection) that can lead to preterm birth. Streptococcus agalactiae or Group B Streptococcus (GBS) is a bacterium that can cause invasive reproductive tract infections that lead to preterm birth. We have new and exciting data indicating females exposed to toxicant have increased susceptibility to GBS infection leading to adverse pregnancy outcomes. We also have strong data showing that toxicant exposure alters placental macrophage antimicrobial activity such as reactive oxygen species production, and GBS survival within macrophages. We also have strong data which supports that macrophages are critical mediators of immune homeostasis during pregnancy that also play a role in invasive GBS infections. Placental macrophages elaborate extracellular traps in response to GBS infectious insult and these traps are decorated with matrix metalloproteinases which are involved in the degradation of cell-to-cell matrices in gestational tissues that are important for maintaining a stable pregnancy. This translational research seeks to understand how toxicant exposure alters host susceptibility to preterm birth (using invasive infection as a model) and contributes to disease progression by modulating the host immune system. This knowledge may lead to new approaches for the prevention and treatment of reproductive tract infections which often lead to preterm birth, neonatal sepsis, maternal bacteremia, and fetal demise as well as ameliorate fertility issues associated with toxicant exposure.

项目摘要 接触持续的环境有毒物质（例如二恶英）是一个全球问题，但不成比例 影响从燃烧坑或橙色衍生的二恶英的退伍军人。二恶英暴露已经 与男性和女性的生育能力降低以及早产的风险增加有关，即使 子宫内发生了暴露。最近的研究表明，女退伍军人的早产风险增加 与最近部署有关，强调需要更好的诊断和干预措施以消除 与退伍军人遇到的独特环境压力源相关的早产风险。 但是，对于导致这种风险的基本分子因素知之甚少。我们假设这一点 接触环境有毒物质导致主机免疫系统的扰动 增加对炎症性损伤的敏感性（例如感染），可能导致早产。 Agalactiae链球菌或B组链球菌（GBS）是一种可能引起侵入性生殖的细菌 导致早产的道感染。我们有新的令人兴奋的数据，表明女性暴露于 毒物对GBS感染的敏感性增加，导致不良妊娠结局。我们也有 强大的数据表明，毒性暴露会改变胎盘巨噬细胞抗菌活性，例如反应性 氧气产生和巨噬细胞中的GBS存活。我们也有强大的数据支持 巨噬细胞是怀孕期间免疫稳态的关键介体，也在 侵入性GBS感染。胎盘巨噬细胞响应GBS的传染性，详细的细胞外陷阱 侮辱和这些陷阱装饰有基质金属蛋白酶，这些酶与降解有关 妊娠组织中的细胞间矩阵对于保持稳定的妊娠很重要。这 转化研究试图了解有毒的暴露如何改变宿主对早产的敏感性 （使用侵入性感染作为模型），并通过调节宿主免疫来促进疾病进展 系统。这些知识可能会导致预防和治疗生殖道的新方法 通常导致早产，新生儿败血症，母体菌血症和胎儿丧生以及 改善与毒物暴露有关的生育问题。