Lead (Pb) toxicity on mechanisms of neurodevelopment by dysregulation of thyroid hormone distributor proteins in Xenopus laevis

项目摘要 在产前和围产期发育过程中环境铅暴露与以下因素的增加有关： 神经发育缺陷和神经异常。虽然长期以来一直认为Pb是 神经毒性，确切的毒性机制尚不完全清楚。以前的研究表明，铅损害 甲状腺激素（TH）生理学。铅致甲状腺激素失调的确切机制 然而，尚未阐明信号传导，TH失调对脑的下游影响， 发展尚未得到评估。因此，拟议研究的目标是调查 铅对甲状腺激素生理和TH介导的脑发育机制的影响。到 为了实现这一目标，汤普森实验室使用了非洲爪蟾蝌蚪，一种经过NIH验证的模式生物 允许发育获得毒理学终点，研究发育接触的影响， 内分泌干扰物对大脑发育的影响根据先前发表的研究表明， 铅影响TH生理的能力，初步实验表明，铅中毒降低表达 两种甲状腺激素分配蛋白（THDPs），甲状腺素运载蛋白和脂质运载蛋白样前列腺素D2合酶， 分别在肝脏和大脑中。THDPs的下调可能会减少TH的量， 到达脑组织。这些变化对大脑发育的具体影响尚未得到评估。 该项目的目的是通过确定生理过程来填补这一重要空白， 铅对TH依赖的细胞和分子发育机制发挥这些作用， 强调神经发育。两栖动物变态试验将用于测试铅中毒 影响整个TH生理学。脑中THDP表达降低的影响将通过以下评估： 定量神经发生、树突分支和TH敏感基因的表达。拟议的工作将 提供了关于HPT轴在发育过程中被Pb失调的方面的信息， 以及这是如何影响大脑发育的各个方面的。这些研究将提供深入了解 铅诱导的神经毒性的机制，并可能为未来的临床研究提供目标， 减少铅中毒对儿童的负面影响。

Project Summary Environmental exposure to lead (Pb) during pre- and perinatal development is associated with an increase in neurodevelopmental deficits and neurological abnormalities. While it has long been established that Pb is neurotoxic, the precise mechanisms of toxicity are not entirely clear. Previous studies showed that Pb impairs thyroid hormone (TH) physiology. The precise mechanisms of Pb-induced dysregulation of thyroid hormone signaling have not been elucidated, however, and the downstream effects of TH dysregulation on brain development have not been assessed. Therefore, the goal of the proposed research is to investigate the effects of Pb on thyroid hormone physiology and on TH-mediated mechanisms of brain development. To address this goal, the Thompson lab has used Xenopus laevis tadpoles, an NIH-validated model organism allowing developmental access to toxicological endpoints, to study the effects of developmental exposure to endocrine disrupting compounds on the developing brain. Based on previously published studies suggesting Pb’s ability to impact TH physiology, Preliminary experiments shows that Pb poisoning decreases expression of two thyroid hormone distributor proteins (THDPs), transthyretin and lipocalin-like prostaglandin D2 synthase, in the liver and the brain, respectively. Downregulation of THDPs likely decreases the amount of TH that reaches brain tissues. The specific effects of these changes on brain development have not been assessed. The aims of this project propose to fill in this important gap by determining the physiological processes by which Pb exerts these effects on TH-dependent cellular and molecular mechanisms of development, with emphasis on neurodevelopment. The Amphibian Metamorphosis Assay will be used to test if Pb poisoning affects overall TH physiology. The effects of decreased THDP expression in the brain will be assessed by quantifying neurogenesis, dendritic arborization, and expression of TH-sensitive genes. The proposed work will provide information regarding the aspects of the HPT axis that are dysregulated by Pb during development as well as how this affects various aspects of brain development. These studies will provide insight into the mechanisms of Pb-induced neurotoxicity and potentially yield a target for future clinical studies aiming to decrease the negative effects of Pb poisoning in children.