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

项目摘要 人们普遍怀疑产前接触化学品会导致神经发育障碍， 将特定的化学物质与不良神经影响联系起来的直接证据很少，而且人们对化学物质的作用知之甚少。 影响大脑发育的机制。迫切需要了解产前 化学品暴露导致神经发育障碍是科学前提 提议我们的初步数据表明，胎盘5-羟色胺（5-HT）的破坏构成了一个潜在的关键， 和神经发育中断的新机制。拟议的研究将检验以下假设： 化学暴露破坏了胎盘和发育中的胎儿之间的肾上腺素能通讯， 前脑导致ASD相关的行为缺陷和受损的突触组织， 神经发育5-HT，来自胎儿胎盘，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，产前接触化学阻燃剂 (FR)混合物Firemaster® 550（FM 550）破坏胎盘5-HT生物合成途径， 男性的焦虑和女性的过度活跃。我们进一步表明，FM 550组件 在大鼠胎盘中生物累积，溴化成分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 表型。我们发现FM 550成分在男性体内的生物累积程度更高， 这与我们在人类中看到的其他FR相似，表明男性暴露的风险更大- 相关后果。这反映了许多神经行为障碍的男性偏见。FM550 含有两种溴化FR和有机磷酸酯FR的混合物，后者具有大体积 FM 550作为增塑剂应用，因此人体接触广泛，并且在FM 550引入之前就已存在。的 这些替代FR的潜在毒性的特征很差。胎盘5-HT的性别特异性破坏 构成了神经发育中断的潜在关键和新机制。 目的1：建立FM 550组分在孕鼠体内的毒代动力学，并定量其对孕鼠的毒性程度。 FM 550在大鼠和人类中的生物累积。 目的2：阐明FM 550干扰胎盘5-HT生物合成和胎盘5-HT能输入的能力。 发育中的前脑 目的3：了解FM 550暴露对神经发育的长期影响， 行为 我们工作的长期目标是阐明产前化学暴露对大脑发育的影响 这样就可以设计出限制接触有害化合物并减轻其有害影响的策略。

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.