The placenta: a novel target of sex specific neurotoxicity by fire retardants

胎盘：阻燃剂性别特异性神经毒性的新靶点

• 批准号: 9975856
• 负责人: Heather B Patisaul
• 金额: $ 44.2万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975856
• 关键词: ASD patient; Anabolism; Animal Behavior; Animal Model; Anxiety; Attention deficit hyperactivity disorder; Behavior; Behavior Disorders; Behavioral; Biological Markers; Brain; Cells; Chemical Exposure; Chemicals; Child; Cognition Disorders; Communication; Data; Deltastab; Development; Disease; Dose; Endocrine disruption; Environment; Environmental Pollution; Esters; Exposure to; Female; Fetal Development; Fetus; Flame Retardants; Goals; Human; Hyperactivity; Incidence; Infant; Life; Link; Neurodevelopmental Disorder; Oral; Organophosphates; Outcome; Parents; Pathway interactions; Pharmacology; Phase; Phenotype; Placenta; Plasticizers; Predisposition; Pregnancy; Prosencephalon; Rattus; Research; Risk; Rodent; Serotonin; Sex Differences; Source; Synapses; Testing; Therapeutic Intervention; Tissues; Toxic effect; Toxicokinetics; Wistar Rats; Woman; Work; autism spectrum disorder; autistic; base; comorbidity; consumer product; developmental neurotoxicity; exposed human population; fetal; male; neurobehavioral disorder; neurodevelopment; neurodevelopmental effect; neurotoxic; neurotoxicity; novel; postnatal; prenatal; prenatal exposure; relating to nervous system; response; screening; sex; trait

Project Summary Prenatal chemical exposures are widely suspected to contribute to risk of neurodevelopmental disorders but direct evidence linking specific chemicals to adverse neural effects is sparse, and very little is known about the mechanisms by which they impact the developing brain. The pressing need to understand how prenatal chemical exposures contribute to disorders of neurodevelopment is the scientific premise for this proposal. Our preliminary data show that disruption of placental serotonin (5-HT) constitutes a potentially key and novel mechanism of neurodevelopmental disruption. The proposed studies will test the hypothesis that chemical exposures disrupt serotonergic communication between the placenta and developing forebrain resulting in ASD-related behavioral deficits and compromised synaptic organization and neurodevelopment. 5-HT, arising from the fetal placenta, has profound effects on the developing brain, particularly forebrain. Our preliminary data in rats shows that prenatal exposure to the chemical flame retardant (FR) mixture Firemaster® 550 (FM550) disrupts the placental 5-HT biosynthetic pathway and results in higher anxiety in males and hyperactivity in females later in life. We further show that FM550 components bioaccumulate in rat placenta and the brominated components transfer across the placenta into the fetus. An important aspect of this proposed work is a focus on sex differences, both in susceptibility and the exposure phenotype. We have found that FM550 components bioaccumulate to a greater degree in males, an outcome similar to what we have also seen for other FRs in humans, suggesting males are at greater risk of exposure- related consequences. This mirrors the male-biased incidence of many neurobehavioral disorders. FM550 contains two brominated FRs and a mixture of organophosphate ester FRs, the latter of which have large volume applications as plasticizers, so human exposure is widespread and predates the introduction of FM550. The potential toxicity of these replacement FRs is poorly characterized. Sex-specific disruption of placental 5-HT constitutes a potentially key and novel mechanism of neurodevelopmental disruption. Aim 1: Establish the toxicokinetics of FM550 components in gestating rats, and quantify the degree to which FM550 bioaccumulates in rats and humans of each sex. Aim 2: Elucidate the capacity of FM550 to disrupt placental 5-HT biosynthesis and serotonergic input on the developing forebrain. Aim 3: Understand the long term impact of developmental FM550 exposure on neural development and behavior. The long term goal of our work is to elucidate the impact of prenatal chemical exposures on brain development so that strategies can be devised to limit exposure to harmful compounds, and mitigate their harmful effects.

项目概要 人们普遍怀疑产前化学物质暴露会导致神经发育障碍的风险，但 将特定化学物质与不良神经影响联系起来的直接证据很少，而且人们对它知之甚少。 它们影响发育中的大脑的机制。迫切需要了解如何产前 化学物质暴露会导致神经发育障碍，这是其科学前提 提议。我们的初步数据表明，胎盘血清素 (5-HT) 的破坏构成了潜在的关键因素。 以及神经发育破坏的新机制。拟议的研究将检验以下假设： 化学物质暴露会破坏胎盘和发育中的血清素通讯 前脑导致 ASD 相关的行为缺陷和突触组织受损 神经发育。 5-HT，源自胎儿胎盘，对发育中的大脑具有深远的影响， 特别是前脑。我们对大鼠的初步数据表明，产前接触化学阻燃剂 (FR) 混合物 Firemaster® 550 (FM550) 会破坏胎盘 5-HT 生物合成途径并导致更高的 男性在晚年生活中会出现焦虑，而女性则会在以后的生活中出现多动症。我们进一步表明 FM550 组件 溴化成分会在大鼠胎盘中生物累积，并通过胎盘转移到胎儿体内。一个 这项拟议工作的一个重要方面是关注性别差异，包括易感性和暴露程度 表型。我们发现 FM550 成分在男性体内的生物累积程度更高，这是一个结果 与我们在人类其他 FR 中看到的情况类似，这表明男性面临更大的暴露风险 - 相关后果。这反映了许多神经行为障碍的发病率偏向男性。 FM550 含有两种溴化阻燃剂和有机磷酸酯阻燃剂的混合物，后者体积较大 作为增塑剂的应用，因此人类接触是广泛的，并且早于 FM550 的推出。这 这些替代阻燃剂的潜在毒性尚不清楚。胎盘 5-HT 的性别特异性破坏 构成神经发育破坏的潜在关键和新颖机制。 目标 1：建立 FM550 成分在妊娠大鼠中的毒代动力学，并量化其毒代动力学程度 FM550 在不同性别的大鼠和人类体内发生生物累积。 目标 2：阐明 FM550 破坏胎盘 5-HT 生物合成和血清素输入的能力 正在发育的前脑。 目标 3：了解发育性 FM550 暴露对神经发育和发育的长期影响 行为。 我们工作的长期目标是阐明产前化学物质暴露对大脑发育的影响 这样就可以制定策略来限制接触有害化合物并减轻其有害影响。