Impact/Purpose:

Research in this area is directed at characterizing the relationship between exposure and adverse endocrine-mediated health outcomes, with an emphasis on enhanced susceptibility during stages of development. Risk assessments for thyroid hormone disruption are hampered by an inability to designate adversity, i.e., to describe the degree to which thyroid hormone must be perturbed in the developing organism to produce neurological deficits. This is owing to inadequate dose-response characterization and a fundamental lack of understanding of the mechanistic links between decreases in thyroid hormone and changes in brain function. Environmental insults produce less severe forms of hypothyroxenemia/hypothyroidism than those described in extant literature on thyroid dysfunction and thus the adverse effects associated with these milder types of insults have yet to be identified. Evidence has been accumulating to indicate that low level maternal thyroid hormone deficiencies in humans can lead to decrements in intellectual function in children, despite normal thyroid function at birth. The overall aim of the present project is to assess the long-term consequences on cognitive function of compounds that produce different magnitudes of thyroid dysfunction by distinct mechanisms during critical periods of brain development.

Description:

SUMMARY: The NTD research project on Endocrine-Disrupting Chemicals (EDC) is focused on the effects of thyroid hormone (TH) deficiencies on the developing brain and is one component of a larger NHEERL research program evaluating androgen, estrogen, and thyroid-disrupting chemicals. Thyroid hormones are essential for brain development, and severe thyroid insufficiency leads to mental retardation associated with cretinism. Environmental exposures, however, typically cause only slight or modest lowering of thyroid hormone, and available data are unclear as to the risks of such a condition. There are two major accomplishments of the NTD research program on thyroid disrupting chemicals. First, the Division has developed a short-term bioassay for identification of thyroid-disrupting chemicals and evaluated the assay with a number of known thyroid-disrupting chemicals, alone and in combinations. Second, in assessing the consequences of moderate thyroid insufficiency on brain development, NTD has found novel alterations in brain morphology, along with deficits in synaptic transmission, plasticity, and behavior. Together, these data will be instrumental in identification of potential thyroid-disrupting chemicals and evaluating their risks at environmental levels of exposure. Thyroid hormones are essential for normal behavioral, intellectual, and neurological development. Severe congenital hypothyroidism results in irreversible structural damage and mental retardation in children. However, more moderate forms of thyroid dysfunction are not without consequence. It is well established that several classes of environmental contaminants can affect thyroid gland morphology and/or hormonal status. This project aims to identify and characterize the functional consequences of developmental hypothyroidism induced by environmental toxicant exposure on the central nervous system (CNS). These effects will be compared and contrasted with those induced by known thyrotoxicants. Current models of hypothyroidism identify specific brain regions that are vulnerable to severe thyroid insult, but little information is available on more mild forms of developmental hypothyroidism. APPROACH: The specific aim of this research project is to expose pregnant rats to known or suspected hypothyroid-inducing xenobiotics that result in different magnitudes of thyroid dysfunction by distinct mechanisms. Chemicals which disrupt thyroid hormone homeostasis by three distinct mechanisms (i.e., synthesis inhibition, induction of catabolic metabolism, uptake blockade) were chosen for study. Assessments of the functional integrity of the auditory system, cerebellum, and hippocampus will be performed in the offspring. These three systems were chosen as they have been shown to be sensitive to hypothyroidism. Offspring will be assessed for CNS dysfunction behaviorally, neurochemically, and electrophysiologically as juveniles and as adults and impairments correlated with the reduction in thyroid hormone levels. Cognition, audition, and hippocampal synaptic function will be examined using preparations that have proved sensitive to more severe forms of hypothyroidism, but which have not been adequately assessed with milder forms of thyroid disruption.

Record Details: