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期间环境铅暴露(铅)与 神经发育缺陷和神经异常。虽然很久以来就已经确定铅是 神经毒性，其确切的毒性机制尚不完全清楚。先前的研究表明，铅会损害人体的健康 甲状腺激素生理学。铅致甲状腺激素失调的确切机制 然而，信号转导机制尚未阐明，TH失调对大脑的下游影响 还没有对发展进行评估。因此，拟议研究的目标是调查 铅对甲状腺激素生理及TH介导的脑发育机制的影响至 为了实现这一目标，汤普森实验室使用了非洲爪哇蝌蚪，这是一种经过美国国立卫生研究院验证的模式生物 允许发育获得毒理学终点，以研究发育暴露于 对发育中的大脑造成内分泌干扰的化合物。基于之前发表的研究表明 铅对TH生理的影响能力，初步实验表明，铅中毒降低了表达 在两种甲状腺激素分配蛋白(THDP)中，转甲状腺素样前列腺素D2合成酶， 分别在肝脏和大脑中。THDP的下调可能会减少THDP的数量 到达脑组织。这些变化对大脑发育的具体影响还没有得到评估。 这个项目的目标是通过确定生理过程来填补这一重要的空白 铅对TH依赖的细胞和分子发育机制产生这些影响， 强调神经发展。两栖变态试验将被用来测试铅中毒 会影响整体的生理。大脑中THDP表达减少的影响将通过以下方式进行评估 量化神经发生、树突分枝和TH敏感基因的表达。拟议的工作将 提供有关在发育过程中受铅失调的HPT轴方面的信息，如 以及这如何影响大脑发育的各个方面。这些研究将为我们提供对 铅诱导神经毒性的机制，并可能为未来的临床研究提供一个靶点，旨在 减少儿童铅中毒的负面影响。

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.