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

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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.