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Gene Expression in Developing Brain is Altered by Modest Reductions in Circulating Levels of Thyroid Hormone.
GILBERT, M. E., K. M. CROFTON, G. Knapp, AND G. M. NELSON. Gene Expression in Developing Brain is Altered by Modest Reductions in Circulating Levels of Thyroid Hormone. Presented at Neurobehavorial Teratology Society (NBTS) Meeting, Louisville, KY, June 26 - 30, 2010.
This research investigated dose-response relationships of TH insufficiency on TH action in developing brain.
Disruption of thyroid hormone (TH) homeostasis is a known effect of environmental contaminants. Although animal models of developmental TH deficiency can predict the impact of severe insults to the thyroid system, the effects of moderate TH insufficiencies have not been adequately addressed. This research investigated dose-response relationships of TH insufficiency on TH action in developing brain. Three methods to perturb the thyroid axis were employed: propylthiouracil (PTU), dietary iodine deficiency, and perchlorate. PTU inhibits TH synthesis; iodine is an essential element for TH synthesis; and perchlorate is an environmental contaminant that blocks iodine uptake. These treatments were delivered via drinking water or food, producing graded levels ofTH reduction during gestation and lactation. TH-responsive genes were examined in cortex of offspring on PNI4. A set of 8 genes that were significantly altered in a gene array analysis by PTU was selected based on the magnitude of change, significance to brain development, and link to thyroid function. Gene-expression was determined using qRT-PCR and used as an estimate of TH action, i.e., an indication of adequate levels of TH in critical target tissues. Dose-dependent reductions in expression of a number of genes were observed that were similar across different modes of thyroid-axis perturbation. Significant reductions were also observed at doses that produced mild reductions in circulating TH in dams or offspring. These findings suggest that autoregulatory mechanisms of the thyroid axis may be insufficient to maintain required tissue levels of TH in the developing brain. (Does not necessarily reflect EPA policy)
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
TOXICOLOGY ASSESSMENT DIVISION