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NEUROPHYSIOLOGICAL CONSEQUENCES IN HIPPOCAMPUS AS A FUNCTION OF DEVELOPMENTAL HYPOTHYROIDISM.
Citation:
Gilbert, M. E. AND L. Sui. NEUROPHYSIOLOGICAL CONSEQUENCES IN HIPPOCAMPUS AS A FUNCTION OF DEVELOPMENTAL HYPOTHYROIDISM. Presented at Endocrins Disruptors Workshop, US EPA, RTP, NC, 10/29-31/2002.
Description:
Thyroid hormones are essential for maturation and function of the mammalian central nervous system. Severe congenital hypothyroidism results in irreversible structural damage and mental retardation in children. Although a variety of environmental contaminants have been demonstrated to alter circulating levels of thyroid hormones (e.g., polychlorinated biphenyls, brominated flame retardants, drinking water contaminants, pesticides), the neurotoxicological effects associated with such hormone reductions have not been adequately assessed. Thyrotoxins such as propylthiouracil (PTU) have been used pervasively in studies designed to determine the role of thyroid hormone in brain development. Although it is well established that the hippocampus is a brain region impacted by hypothyroidism, functional assessment of the neurophysiological integrity of the hippocampus following such treatment is lacking. Moreover, little information is available on more modest perturbations in thyroid hormones that would mimic those induced by environmental agents. This presentation will focus on recent data from our laboratory characterizing the physiological changes associated with developmental hypothyroidism induced by PTU. Synaptic transmission and plasticity in the dentate gyrus of the hippocampus of adult offspring of pregnant dams treated with A1254 and PTU are clearly altered, but the pattern of change is distinct between these two types of treatment. The age and duration of exposure, the age and site of assessment, and the relative change in the two main thyroid hormones, T3 and T4, may all contribute to differential patterns of effects observed. Differential effects are also evident between the CA1 and dentate subregions of the hippocampus. However, certain similarities also exist, a predominant feature being the irreversible nature of the developmental insult in a brain region critical for cognitive function. Exposure limited to the perinatal period produced alterations in synaptic transmission and plasticity in adulthood despite elimination of the contaminant and a return of thyroid hormones to normal range. Future work will extend these observations by characterizing more fully the dose-response relationships, examining behavioral correlates of altered physiology, and evaluating environmentally significant thyroid-disrupting chemicals including brominated flame retardants and perchlorate. Increased understanding of the long term consequences of mild perturbation of thyroid hormones during brain development will aid in assessment of the potential health hazards posed by environmental contaminants that interfere with thyroid hormone function. (This abstract does not necessarily reflect EPA policy)