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: 10553139
• 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/10553139
• 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; DNA; Data; Developmental Process; Diagnostic; Dioxins; Disease Outcome; Disease Progression; Endocrine Disruptors; Environment; Environmental Pollutants; 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; Invaded; Iraq; Knowledge; Link; Macrophage; 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; Repression; Reproductive Health; Reproductive Process; Reproductive Tract Infections; Research Proposals; Risk; Role; Streptococcal Infections; Streptococcus Group B; Tetrachlorodibenzodioxin; Therapeutic Intervention; 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; 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.

项目概要 接触持久性环境毒物（如二恶英）是一个全球性问题，但不成比例 影响接触过来自烧伤坑或橙剂的二恶英的退伍军人。二恶英暴露已 与男性和女性的生育能力下降和早产风险增加有关，即使 暴露发生在子宫内。最近的研究表明，女性退伍军人早产的风险增加 与最近的部署相关，强调需要更好的诊断和干预措施来消除 退伍军人遇到的独特环境压力因素导致早产的风险。 然而，人们对导致这种风险的潜在分子因素知之甚少。我们假设 接触环境毒物会导致宿主免疫系统程序受到干扰，从而导致 增加对炎症损伤（例如感染）的易感性，从而导致早产。 无乳链球菌或 B 族链球菌 (GBS) 是一种可导致侵入性生殖的细菌 导致早产的肠道感染。我们有新的令人兴奋的数据表明女性暴露于 有毒物质增加了 GBS 感染的易感性，导致不良妊娠结局。我们还有 强有力的数据表明，有毒物质暴露会改变胎盘巨噬细胞的抗菌活性，例如反应性 巨噬细胞内氧气的产生和 GBS 的存活。我们还有强大的数据支持 巨噬细胞是妊娠期间免疫稳态的关键介质，在 侵袭性 GBS 感染。胎盘巨噬细胞精心设计细胞外陷阱以应对 GBS 感染 侮辱，这些陷阱装饰有基质金属蛋白酶，参与降解 妊娠组织中的细胞间基质对于维持稳定妊娠非常重要。这 转化研究旨在了解有毒物质暴露如何改变宿主对早产的易感性 （使用侵袭性感染作为模型）并通过调节宿主免疫促进疾病进展 系统。这些知识可能会带来预防和治疗生殖道疾病的新方法 经常导致早产、新生儿败血症、母体菌血症和胎儿死亡的感染 改善与有毒物质接触相关的生育问题。