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Gene Expression as a Biomarker of Effect of Thyroid Hormone Action in Developing Brain: Relation to Serum Hormones.
Knapp, G., G. Nelson, K. M. CROFTON, AND M. E. GILBERT. Gene Expression as a Biomarker of Effect of Thyroid Hormone Action in Developing Brain: Relation to Serum Hormones. Presented at Society of Toxicology (SOT) Annual Meeting, Washington, DC, March 06 - 10, 2011.
This research investigated dose-response relationships of TH insufficiency with the aim of identifying biomarkers of effect of 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 proved more difficult to assess. This research investigated dose-response relationships of TH insufficiency with the aim of identifying biomarkers of effect of TH action in developing brain. The thyroid axis was perturbed by administering propylthiouracil (PTU, 0 1 2 3 ppm) or perchlorate (0 1 30 300 1000 ppm), delivered via drinking water to the dam from early gestation (GD6) until pups were weaned on postnatal day 21 (PN2l). These treatments induced graded levels of T4 reduction in the dam. Pups were differentially affected -PTU reduced T4 on PN14, perchlorate had only minimal impact. A suite of 8 TH-sensitive genes, selected from a previous microarray analysis with PTU, were examined in cortex and hippocampus of PN14 offspring. 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. No changes were seen in the hippocampus of pups from either treatment. Dose-dependent reductions in expression of hr, parvalbumin, hod, co111a, however, were observed in the cortex. Significant changes in cortical gene expression were observed at doses that did not alter serum T4 in dams (l ppm PTU or perchlorate), and produced mild (1 ppm PTU) or no changes in T4 in PN14 pups (Perchlorate). These findings indicate that the cortex may be more sensitive than hippocampus for identifying biomarkers of effect of TH action; serum T4 was not predictive of gene expression changes in all cases; and autoregulatory mechanisms of the thyroid axis may be insufficient to maintain required tissue levels of TH in the developing cortex. (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