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CHEMICALS THAT DISRUPT THE THYROID AXIS: COLLABORATION BETWEEN ORD AND STAR GRANT RECIPIENTS.
Citation:
GILBERT, M. E., K. M. CROFTON, M. J. DEVITO, R. T. ZOELLER, J. W. FISHER, D. FERGUSON, J. WAGNER, AND S. LAESSIG. CHEMICALS THAT DISRUPT THE THYROID AXIS: COLLABORATION BETWEEN ORD AND STAR GRANT RECIPIENTS. Presented at EPA Science Forum, Washington, DC, May 16 - 18, 2006.
Description:
For effective regulation, the EPA must determine the potential adverse consequences of mild disturbances of the thyroid axis on brain development. Severe hypothyroidism has long been known to lead to profound alterations in brain development and mental retardation. However, the specific molecular and cellular consequences of developmental hypothyroidism on subsequent central nervous system function is relatively uncharacterized.
The National Health and Environmental Effects Research Laboratory (NHEERL) has three laboratories working to establish the relationship between the degree of thyroid hormone disruption and adverse neurological outcomes using a variety of xenobiotics. The goal of this work is to relate perturbations of thyroid hormone homeostasis to disruptions in brain function by evaluating behavioral, physiological, and anatomical measures. NHEERL is examining serum levels of thyroid hormones in rats because this metric is also available in humans. For example, the degree of serum hormone insufficiency induced by xenobiotics during development has been correlated with hearing loss. This impairment in rodent models occurs at moderate levels of hormone deprivation, but is not commonly observed in humans following exposures to environmental contaminants. Therefore, animal models of low-level perturbation of the thyroid axis are needed to mimic the mild degrees of hormonal insufficiency induced by xenobiotics and the health outcomes of concern in humans (i.e., cognitive impairment).
A collaboration between EPA scientists at NHEERL and two Science-To-Achieve-Results (STAR) researchers is investigating the dose-response relationships of thyroid toxicants to neurological impairment, especially at lower doses than have traditionally been assessed in toxicological studies. The goals of the individual projects are (1) to develop and validate biomarkers of thyroid disruption, such as changes in gene and protein expression in the brain and (2) to develop and validate a biologically based pharmacokinetic model for the thyroid hormone axis in the pregnant rat. Together, the STAR investigators and EPA scientists have coordinated their experimental designs, chemical selection, and dosing paradigms and have shared animals and tissues from experiments with similar treatment regimens. Data from molecular, cellular, physiological, anatomical, and behavioral indices of neurotoxicity will be shared across laboratories. This synergistic effort between the STAR investigators and EPA scientists will substantially enhance the biological database available to discern the health risks associated with thyroid hormone disruption. The cross-laboratory collaboration will permit linkage of molecular events to adverse clinical outcomes of concern and enable development of a more comprehensive mode-of-action model for low-level thyroid disruption.
(This abstract does not reflect EPA policy)