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The Nature of Compensatory Response to Low Thyroid Hormone in Developing Brain.
SHARLIN, D. S., M. E. GILBERT, M. TAYLOR, D. FERGUSON, AND R. T. ZOELLER. The Nature of Compensatory Response to Low Thyroid Hormone in Developing Brain. NEUROENDOCRINOLOGY. Karger Libri AG, Basel, Switzerland, 22(3):153-165, (2010).
The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis. The existing literature identifies morphological and neurochemical indices of severe neonatal hypothyroidism in the early postnatal period in classic animal models of hypothyroidism. Few data are available on the impact of more modest disruptions of the thyroid axis as would be expected to accompany exposure to environmental contaminants. Specifically, the degree to which the developing brain is sensitive to small reductions in serum thyroid hormone has not been established. EPA has awarded a STAR grant to study the effects low level thyroid hormone disruption on neurodevelopment. This grant was converted into a Cooperative Agreement and strong collaborative ties were established between the grantee and NHEERL scientists. The present manuscript is the result of this collaborative effort and has explored the ability of putative compensatory mechanisms in the developing organism to prevent adverse consequences of small reductions in serum thyroxin. Graded levels of thyroxine reductions were induced using doses of propylthiouracil (PTU) at concentrations more than 200-fold lower than those traditionally used in standard hypothyroid models. A number of measures of compensatory function were demonstrated including increases in thyroid stimulating hormone (TSH), upregulation of brain deiodinase, increased expression in the hormone transporter protein MCT8 in cortical neurons. However, despite these adaptive responses, expression of a T3-senstivie gene, RC3, was still reduced in cortical neurons. These findings clearly indicated that the developing rat brain has a limited capacity to compensate for low serum thyroid hormone. These findings indicate that subclinical hypothyroidisim should not be ruled out as a potential adverse situation and that the neonate does not have as large a capacity to compensate for low thyroid hormone as previously presumed. If a similar situation also occurs in humans, it should not be assumed that there are robust mechanisms in place to provide adequate protection during critical periods of brain development. Note: In initial pilot experiments described in this manuscript, one condition include exposure to a high dose of perchlorate in combination with methimazole (thyroid hormone synthesis inhibitor) to produce a severe state of hypothyroidism. The focus of this paper is not on perchlorate but on modest levels of hormone disruption induced by low doses of a propylthiouracil, a pharmacological not an environmental agent.
Abstract Thyroid hormone is essential for normal brain development, but the degree to which the developing brain is sensitive to small perturbations in serum thyroxin is not clear. An important concept related to this is that the developing brain possesses potent mechanisms to compensate for low serum thyroid hormone, and this concept is routinely employed in discussions concerning clinical treatments or public health. However, experimental studies have not directly tested whether, or the degree to which, putative compensatory mechanisms can ameliorate the consequences of small reductions in serum T(4). To formally test this concept, we employed a model of graded T(4) reductions using doses of propylthiouracil (PTU) 200- to 67-fold lower than the dose traditionally used to produce hypothyroidism in rats. PTU produced a step-wise decrease in serum total T(4), and a step-wise increase in serum TSH, in D2 mRNA expression and enzyme activity in the brain, and in the expression of the mRNA encoding the T(3) transporter MCT8 in the postnatal 15 day cortex. However, the mRNA encoding RC3/Neurogranin, a direct target of T(3) action, exhibited a strong negative linear correlation with serum total T(4) despite these adaptive responses. In addition, single-cell analysis of RC3 mRNA levels in cortical neurons demonstrated that the co-expression of MCT8 did not alter the relationship between RC3 mRNA and serum T(4). These findings do not support the concept as it is currently envisioned that the developing brain is capable of compensating for low T(4).
Record Details:Record Type: DOCUMENT (JOURNAL/NON-PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
NEUROPHYSIOLOGICAL TOXICOLOGY BRANCH