PCB-mediated dysbiosis of the gut microbiome: A missing link in PCB-mediated neurodevelopmental disorders?

项目总结/摘要 发育中的大脑暴露于多氯联苯（PCB）和肠道微生物组的破坏 已经独立地涉及神经发育障碍（NDD）的病因学。这两种现象 可能通过两种机制相互作用，导致不良的神经发育结果： 肠道微生物组（1）改变分布到发育中的大脑的神经活性微生物代谢物的分布， (2)通过改变宿主和微生物的PCB代谢来影响PCB在发育中的大脑中的处置。一种机械的 了解这些相互作用是必要的，以解决干预策略的关键需求， 有效减少多氯联苯引起的NDD对个人、家庭和社会的影响。长期目标是-- 确定肠道微生物组-肝-脑轴在调节PCB对发育影响的易感性中的作用， 的目的是表征母体暴露于 环境相关的PCB混合物和肠道微生物组影响传统的神经毒性结果 (CV)与无菌（GF）幼年小鼠相比。我们将检验核心假设，即肠道微生物组的生态失调是- 与发育接触不同剂量的多氯联苯有助于不利的神经发育外， 在以后的生活中。这一假设是基于初步的研究表明：（1）多氯联苯暴露的原因 肠道微生物组的生态失调;（2）多氯联苯及其代谢物存在于啮齿动物大脑中;（3）多氯联苯的表达 CV和GF小鼠的PCB代谢酶的差异;（4）CV和GF小鼠的PCB处置不同 （5）多氯联苯对小鼠具有发育神经毒性。在这些初步数据的指导下，新的hy- 假设将通过以下方式进行测试：（a）表征肠道微生物组组成和功能以及神经活性微生物 （B）确定宿主与微生物生物转化的差异如何影响多氯联苯的处置， 它们的代谢物;以及（c）检查神经炎症、氧化应激、突触连接和神经细胞的行为。 母鼠和胎儿/幼崽来自（i）CV与GF母鼠暴露于饮食中的PCB，以及（ii）GF母鼠重新暴露于PCB， 从暴露于PCB或溶剂对照CV母鼠中接受粪便移植。该研究具有创新性 因为它在最先进的小鼠模型中使用了系统生物学方法来评估肠道MI的作用， crobiome-liver-brain axis in modulating neurotoxic outcomes after exposure to an environmental PCB mix- 是的。这些研究的预期结果是一个新的研究范式，表明发展 暴露于PCB介导（1）肠道微生物组组成和功能的纵向变化，（2）改变 PCB在发育中的大脑中的分布影响以后的神经发育结果。这一结果 将对公共卫生产生重大影响，为未来研究细胞机制的发展提供信息， PCB神经毒性的opmental起源，并最终提供关于微生物毒性的可接受性的重要见解。 以生物群系为基础的方法来诊断和治疗由暴露于神经毒物引起的NDD。

PROJECT SUMMARY/ABSTRACT Exposure of the developing brain to polychlorinated biphenyls (PCBs) and disruption of the gut microbiome have independently been implicated in the etiology of neurodevelopmental disorders (NDDs). Both phenomena likely interact by two mechanisms to cause adverse neurodevelopmental outcomes: PCB-mediated changes in the gut microbiome (1) alter the profile of neuroactive microbial metabolites distributed to the developing brain and (2) affect PCB disposition in the developing brain by modifying host and microbial PCB metabolism. A mechanistic understanding of these interactions is required to address the critical need for interventional strategies that effec- tively reduce the impact of PCB-induced NDDs on individuals, families, and society. The long-term goal is to de- termine the role of the gut microbiome–liver–brain axis in modulating susceptibility to PCB effects on the develop- ing brain, with the objective of characterizing how dose-dependent interactions between maternal exposure to an environmentally relevant PCB mixture and the gut microbiome influence neurotoxic outcomes in conventional (CV) vs. germ-free (GF) juvenile mice. We will test the central hypothesis that dysbiosis of the gut microbiome as- sociated with developmental exposure to varying doses of PCBs contributes to adverse neurodevelopmental out- comes later in life. This hypothesis is based on preliminary studies showing that: (1) PCB exposure causes dysbiosis of the gut microbiome; (2) PCBs and their metabolites are present in the rodent brain; (3) the expression of PCB-metabolizing enzymes differs between CV vs. GF mice; (4) PCB disposition differs between CV and GF mice; and (5) PCBs are developmental neurotoxicants in mice. Guided by these preliminary data, the novel hy- pothesis will be tested by (a) characterizing gut microbiome composition and function and neuroactive microbial metabolites; (b) determining how differences in host vs. microbial biotransformation affect disposition of PCBs and their metabolites; and (c) examining neuroinflammation, oxidative stress, synaptic connectivity, and behavior in dams and fetuses/pups derived from (i) CV vs.GF dams exposed to PCBs in the diet and (ii) GF dams who re- ceived a fecal transplant from PCB-exposed or vehicle control CV dams. The proposed research is innovative because it uses a systems biology approach in a state-of-the-art mouse model to assess the role of the gut mi- crobiome–liver–brain axis in modulating neurotoxic outcomes following exposure to an environmental PCB mix- ture. The anticipated outcome of these studies is a new research paradigm demonstrating that developmental exposures to PCBs mediate (1) longitudinal changes in gut microbiome composition and function and (2) alter PCB disposition in the developing brain that influence neurodevelopmental outcomes later in life. This outcome will have a significant impact on public health by informing future studies of cellular mechanisms of the devel- opmental origin of PCB neurotoxicity and, ultimately, provide critical insights regarding the plausibility of micro- biome-based approaches to diagnose and treat NDDs induced by exposure to neurotoxicants.