Toxicant Exposure Impacts Host-pathogen interactions within the Reproductive Tract

项目摘要 暴露于持久性环境毒物（如二恶英）是一个全球性问题， 影响暴露于燃烧坑或橙子剂中的二恶英的退伍军人。戴奥辛暴露 与男性和女性的生育能力下降和早产风险增加有关， 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 与最近的部署有关，强调需要更好的诊断和干预措施， 早产的风险与退伍军人遇到的独特环境压力有关。 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 暴露于环境毒物导致宿主免疫系统程序的扰动， 增加对炎性损伤（如感染）的易感性，可导致早产。 无乳链球菌或B族链球菌（GBS）是一种可引起侵入性生殖道感染的细菌， 导致早产的肠道感染。我们有新的令人兴奋的数据表明， 有毒物质增加了对GBS感染的易感性，导致不良妊娠结局。我们也有 强有力的数据表明，毒物暴露改变了胎盘巨噬细胞的抗微生物活性， 氧物质产生和巨噬细胞内GBS存活。我们也有强有力的数据支持 巨噬细胞是妊娠期间免疫稳态的关键介质， 侵袭性GBS感染胎盘巨噬细胞精心制作细胞外陷阱以响应GBS感染 这些陷阱被基质金属蛋白酶装饰，这些基质金属蛋白酶参与降解 妊娠组织中的细胞间基质，这对维持稳定妊娠很重要。这 转化研究旨在了解毒物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而促进疾病进展 系统这些知识可能会导致新的方法来预防和治疗生殖道疾病 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，以及 改善与毒物接触相关的生育问题。

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.