BPA effects on the gut microbiome

围产期暴露于环境相关剂量的双酚A（BPA）， 在我们的CD-1小鼠模型中，人类胎儿发育的变化导致了一种复杂的综合征， 生育能力、行为、身体成分、葡萄糖稳态、代谢特征和增加的倾向， 乳腺癌这些影响归因于BPA对靶器官的直接作用;然而， 影响可能是由于BPA引起的母亲的改变，包括她的行为，循环， 激素水平和肠道微生物组。在一项初步研究中，成年女性围产期暴露于 结果显示，有益细菌减少，肠道相关细菌的差异 病理学，这表明这些变化可能有助于BPA暴露的一些影响。还 在研究的所有时间点，这些小鼠的代谢组学特征与对照组不同。因为肠道微生物 影响代谢组，我们将探讨BPA暴露，肠道微生物组变化和 血清代谢组代谢组学分析将用作微生物组状态的独立标志物。 我们假设：1）围产期BPA改变了暴露后代及其母亲的肠道微生物组; 2)暴露于BPA的后代的代谢组学特征将反映肠道微生物群的变化， BPA暴露和肠道微生物组组成的标志物。具体目标1：探讨假设， BPA暴露改变了围产期暴露于BPA的雌性和雄性后代的肠道微生物群。的 将在PND 15、PND 28和PND 3时分析雄性和雌性后代的粪便提取物中的微生物组， 月龄。此外，将在妊娠结束时分析其母亲的粪便提取物， 在哺乳期（LD 15）检查母体的影响，可能会传递给后代。测序数据 将进行分析，以确定BPA暴露和对照动物的差异丰富的功能。具体目标 2探讨了代谢组学分析提供微生物组健康的生物标志物的假设， 早期BPA暴露NMR代谢指纹将用于关联微生物组和代谢组 具体目标1中研究的后代的变化。首先，我们要区分不同的群体。接下来，NMR和 HRMS代谢组学谱将用于重建不同处理小鼠的“代谢网络” 组最后，我们将确定具有生物学意义的子网络，例如，可能是 由于BPA暴露对肠道微生物群（短链脂肪酸、血清素、丁酸盐等）的影响， 这些探索性研究将描述围产期BPA暴露对肠道微生物群的影响， 确定微生物群组成的变化是否可能导致BPA的某些不利影响 包括在我们的动物中一直观察到的改变的代谢组学特征。这些发现可能会发现一个 BPA作用的新靶点以及指导和评估未来治疗的可靠代谢组学标志物 干预措施（例如给予益生菌等）来改善BPA综合症的症状

Perinatal exposure to environmentally relevant doses of bisphenol-A (BPA) during a period comparable to that of human fetal development causes a complex syndrome in our CD-1 mouse model that includes alterations in fertility, behavior, body composition, glucose homeostasis, metabolic profiles and increased propensity to mammary cancer. These effects were attributed to direct action of BPA on target organs; however, indirect effects may result from BPA-induced alterations in the mother, including changes in her behavior, circulating hormone levels and gut microbiome. In a pilot study, the fecal microbiota in adult females exposed perinatally to BPA revealed a decrease in beneficial bacteria and differences in bacteria associated with intestinal pathology, suggesting that these alterations may contribute to some effects of BPA exposure. Also, the metabolomic profiles of these mice differ from controls at all time-points studied. Because the gut microbiome affects the metabolome, we will explore the potential link between BPA exposure, gut microbiome changes and the serum metabolome. Metabolomic profiling will be used as an independent marker of microbiome status. We hypothesize that: 1) perinatal BPA alters the gut microbiome of exposed offspring and their mothers; and 2) the metabolomic profiles of the BPA exposed offspring will reflect changes in the gut microbiota and provide a marker of BPA exposure and gut microbiome composition. Specific Aim 1: explores the hypothesis that BPA exposure alters the gut microbiota of female and male offspring exposed perinatally to BPA. The microbiome will be analyzed in fecal extracts of male and female offspring at PND 15, PND 28, and at 3 months of age. Additionally, fecal extracts from their mothers will be analyzed at the end of gestation and during lactation (LD15) to examine maternal effects that may be transmitted to the offspring. Sequencing data will be analyzed to identify differentially abundant features in BPA exposed and control animals. Specific Aim 2 explores the hypothesis that metabolomics profiling provides a biomarker of microbiome health and early BPA exposure. NMR metabolic fingerprints will be used to correlate microbiome and metabolome changes in the offspring studied in Specific Aim 1. First, we will discriminate between groups. Next, NMR and HRMS metabolomic profiles will be used to reconstruct “metabolic networks” of mice from different treatment groups. Finally, we will identify sub-networks of biological significance e.g. the metabolic pathways that may be shifted due to effects of BPA exposure on the gut microbiota (short chain fatty acids, serotonin, butyrate, etc). These exploratory studies will delineate the effects of perinatal BPA exposure on the gut microbiota to determine whether changes in microbiota composition may contribute to some adverse effects of BPA including the altered metabolomic profiles consistently observed in our animals. These findings may identify a new target of BPA action as well as reliable metabolomics markers to guide and evaluate future therapeutic interventions (e.g. administration of pro-biotics,etc.) to ameliorate components of the BPA syndrome.