Science Inventory

Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Make Rats

Citation:

Gilbert, M., K. Sanchez-Huerta, AND C. Wood. Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Make Rats. ENDOCRINOLOGY. Endocrine Society, 157(2):774-87, (2016).

Impact/Purpose:

The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone (TH) homeostasis. To determine the degree to which serum TH can be reduced by environmental exposures without resulting in adverse neurological consequences, it is essential to identify sensitive targets of TH action that when perturbed disrupt brain function. The existing literature on TH disruption in brain shows that many facets of brain development are perturbed, but while some are directly linked to TH, others result from indirect effects associated with the severity of the insult induced in these models. Our work has focused on characterization of a low dose model of TH disruption that more closely aligns with the magnitude of TH insufficiency typical of that induced by xenobiotics.

Description:

Severe thyroid hormone (TH) deficiency during critical phases of brain development results in irreversible neurological and cognitive impairments. The mechanisms accounting for this are likely multifactorial, and are not fully understood. Here we pursue the possibility that one important element is that TH affects basal and activity-dependent neurotrophin expression in brain regions important for neural processing. Graded exposure to propylthiouracil (PTU) during development produced dose-dependent reductions in mRNA expression of nerve growth factor (Ngf) in whole hippocampus of neonates. These changes in basal expression persisted to adulthood despite the return to euthyroid conditions in blood. In contrast to small PTU-induced reductions in basal expression of several genes, developmental PTU treatment dramatically reduced the activity-dependent expression of neurotrophins and related genes (Bdnft, Bdnfiv, Arc, and Klf9) in adulthood and was accompanied by deficits in hippocampal-based learning. These data demonstrate that mild TH insufficiency during development not only reduces expression of important neurotrophins that persists into adulthood but also severely restricts the activity­ dependent induction of these genes. Considering the importance of these neurotrophins for sculpting the structural and functional synaptic architecture in the developing and the mature brain, it is likely that TH-mediated deficits in these plasticity mechanisms contribute to the cognitive deficiencies that accompany developmental TH compromise.

URLs/Downloads:

http://dx.doi.org/10.1210/en.2015-1643   Exit

Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Product Published Date: 02/01/2016
Record Last Revised: 11/21/2017
OMB Category: Other
Record ID: 312291

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY

TOXICOLOGY ASSESSMENT DIVISION

ENDOCRINE TOXICOLOGY BRANCH