Toxicokinetics and Metabolic Disrupting Actions of the Flame Retardant Mixture FM

美国的肥胖率已经达到了流行的程度。尽管生活方式因素显然是 主要贡献者，由环境化学品共同进行的胎儿代谢重新编程 所谓的“肥胖症”被认为会加剧肥胖风险。数据协作 由三个共同的PI生成的已经确定了新引入的阻燃混合物 Firemaster®550(FM 550)是美国家庭和围产期(老鼠)中的一种新污染物 暴露于FM 550会导致肥胖和代谢综合征的特征，包括改变 探索性行为、葡萄糖敏感性紊乱和心肌肥大。有压迫感 需要评估FM 550的毒性，因为它至少是第二种最常见的火灾 阻燃剂用于住宅家具和婴儿产品，在美国随处可见，但 其潜在的毒理学效应尚未得到很好的描述。作为一个跨学科、多领域的 PI小组，由一名环境化学家、一名神经内分泌学家和一名内分泌人员组成 药剂学家，我们提交了一份R01申请，以测试FM 550是一种 肥胖和围产期暴露会诱发代谢综合征的特征(例如高血压、 二型糖尿病和心血管疾病)通过代谢再编程。为了加强R01 应用程序并生成解决审阅者问题所需的附加数据，在此版本56中工作 应用将(1)表征FM 550在雌性大鼠(怀孕和非妊娠)中的毒代动力学。 怀孕)具体评估移植胎儿的可能性；和(2)描述特征 FM550(单剂量)对两者子代的代谢干扰和行为影响 性别。重要的是，无论体重的增加(在 在我们的初步研究中观察到的父母R01)伴随着食物摄入量和/或 总体活动的变化将被确定。这些都是新陈代谢的关键标志 重新编程，从而将有助于解决父R01的中心假设，即FM550是 一种“肥胖症”，可能使暴露于此的后代易患代谢性疾病。检视 表型性别差异是这项应用的一个基本特征，数据最终将 被用来为未来的工作(以及R01应用程序的具体目标)探索性 FM550，ITS成脂作用和代谢干扰活性的具体机制 成分和主要代谢物。了解每个FM 550的贡献 导致肥胖表型的成分是至关重要的，因为一些成分具有大量的应用 作为各种消费品中的增塑剂(例如聚氯乙烯(PVC)、电路 板材、液压油、粘合剂、指甲油)。总的来说，拟议的研究将有助于 对我们为这项工作获得R01资金的长期努力，也提供了新的知识 评估发育期FM 550暴露对人类健康的潜在影响所需 包括：组织中的去向和转运；混合物及其个体的致胖潜力 广泛剂量范围内的成分；特定性别的作用机制；以及可能的长时间 两性早年暴露的足月代谢健康后果。

Obesity rates in the US have reached epidemic proportions. Although lifestyle factors are clearly primary contributors, fetal metabolic reprogramming by environmental chemicals collectively called “obesogens” has been hypothesized to exacerbate obesity risk. Data collaboratively generated by the three co-PIs have identified the newly introduced fire retardant mixture Firemaster® 550 (FM 550) as an emerging contaminant in US homes and that (in rats) perinatal exposure to FM 550 results in obesity, and hallmarks of metabolic syndrome including altered exploratory behaviors, disrupted glucose sensitivity and cardiac hypertrophy. There is pressing need to assess the toxicity of FM 550 because it is at least the second most common fire retardant used in residential furniture and baby products with ubiquitous exposure in the US, yet its potential toxicological effects are not well characterized. Working as an interdisciplinary, multi- PI team, comprising an environmental chemist, a neuroendocrinologist and an endocrine pharmacologist, we submitted an R01 application to test the hypothesis that FM 550 is an obesogen, and perinatal exposure induces hallmarks of metabolic syndrome (e.g. hypertension, type-2 diabetes and cardiovascular disease) via metabolic reprograming. To strengthen the R01 application and generate additional data required to address reviewer concerns, work in this R56 application will (1) characterize the toxicokinetics of FM 550 in female rats (pregnant and non- pregnant) to specifically assess the potential for fetal transfer; and (2) characterize the hallmarks of metabolic disrupting and behavioral effects of FM550 (one dose) in exposed offspring of both sexes. Importantly, whether or not the increase in body weight (identified as sexually dimorphic in the parent R01) observed in our pilot study is accompanied by increased food intake and/or changes in overall activity will be determined. These are key markers of metabolic reprogramming and will thus help address the central hypothesis of the parent R01 that FM550 is an “obesogen” and can predispose exposed offspring to metabolic disease. Examining phenotypic sex differences is a fundamental feature of this application, and the data will ultimately be used to inform future work (and a specific aim of the R01 application) exploring the sex specific mechanisms underlying adipogenesis and the metabolic disrupting activity of FM 550, its components, and primary metabolites. Understanding the contributions of each FM 550 component to an obesogenic phenotype is critical because some have large volume applications as plasticizers in a wide variety of consumer products (e.g. polyvinyl chloride (PVC), circuit boards, hydraulic fluids, adhesives, nail polish). Collectively the proposed studies will contribute to our long term efforts to secure R01 funding for this work but also provide new knowledge required for evaluating potential human health effects of developmental FM 550 exposures including: fate and transport in tissues; obesogenic potential of the mixture and its individual components across a wide dose range; sex-specific mechanism of action; and the possible long term metabolic health consequences of early life exposure in both sexes.