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

项目摘要 产前接触化学物质被广泛怀疑会增加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，而且对 它们影响发育中大脑的机制。迫切需要了解产前是如何 化学暴露会导致神经发育障碍是这一点的科学前提 求婚。我们的初步数据显示，胎盘5-羟色胺(5-HT)的紊乱是一个潜在的关键 以及神经发育障碍的新机制。拟议的研究将检验这一假设 化学物质暴露扰乱胎盘和发育中的5-羟色胺能通讯 前脑导致ASD相关行为缺陷和突触组织受损 神经发育。来自胎儿胎盘的5-羟色胺对发育中的大脑有深远的影响， 尤其是前脑。我们在老鼠身上的初步数据显示，出生前接触这种化学阻燃剂 (FR)混合物Firemaster®550(FM550)扰乱胎盘5-羟色胺的生物合成途径，导致更高的 男性的焦虑和女性晚年的多动症。我们进一步证明了FM550组件 在大鼠胎盘中生物积累，溴化成分通过胎盘转移到胎儿。一个 这项拟议工作的重要方面是关注性别差异，无论是在易感性方面还是在接触方面。 表型。我们已经发现，FM550成分在男性体内的生物积累程度更高，这是一个结果 类似于我们在人类身上也看到的其他FR，这表明男性接触的风险更大- 相关后果。这反映了许多神经行为障碍的男性偏向发病率。FM550 含有两种溴化FRS和一种有机磷酸酯FRS的混合物，后者体积较大 作为增塑剂的应用，因此人体接触是广泛的，早在引入FM550之前。这个 这些替代FRS的潜在毒性特征很差。胎盘5-羟色胺的性别特异性破坏 构成了神经发育障碍的潜在关键和新机制。 目的1：建立FM550组分在妊娠大鼠体内的毒代动力学，并量化其对孕鼠的影响程度。 FM550在不同性别的大鼠和人类体内生物积累。 目的2：阐明FM550对胎盘5-羟色胺生物合成和5-羟色胺能输入的干扰作用 发育中的前脑。 目标3：了解发育期FM550暴露对神经发育和 行为。 我们工作的长期目标是阐明产前接触化学物质对大脑发育的影响 因此，可以制定战略，限制接触有害化合物，并减轻其有害影响。

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.