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Magnetic Resonance Imaging and Volumetric Analysis: Novel Tools to Study Thyroid Hormone Disruption and Its Effect on White Matter Development
Powell, M., H. Nguyen, M. Gilbert, M. Parekh, L. Colon Perez, T. Mareci, AND E. Montie. Magnetic Resonance Imaging and Volumetric Analysis: Novel Tools to Study Thyroid Hormone Disruption and Its Effect on White Matter Development. NEUROTOXICOLOGY. Intox Press, Inc, Little Rock, AR, 33(5):1322-9, (2012).
Humans and wildlife are exposed to environmental pollutants that have been shown to interfere with the thyroid hormone system and thus may affect brain development. Our goal was to expose pregnant rats to propylthiouracil (PTU) to measure the effects of a goitrogen on white matter development in offspring using magnetic resonance imaging (MRI) and volumetric analysis. We exposed pregnant Sprague Dawley (SD) rats to 3 or 10 ppm PTU from gestation day 7 (GD7) until postnatal day 25 (P25) to determine the effects on white matter (WM), gray matter (GM), and hippocampus volumes in offspring. We sacrificed offspring at P25 but allowed some individuals to live to P90 to measure persistent effects in adult animals. P25 offspring exposed to 10 ppm PTU displayed lowered levels oftriiodothyronine (T3) and thyroxine (T4); cerebral WM, GM, and total brain volumes were significantly lower than the volumes of control animals. P90 adults exposed to 10 ppm PTU displayed normal T3 levels but lowered T4levels; WM, GM, total brain, and hippocampal volumes were significantly lower than the volumes ofcontrol adults. A significant reduction in percent WM was observed in both P25 and P90 rats exposed to 10 ppm PTU; 3 ppm exposure produced no significant effects. Additionally, heterotopias in the corpus callosum were observed in rats exposed to 10 ppm PTU. These results suggest that MRI coupled with volumetric analysis is a powerful tool in assessing the effects ofthyroid hormone disruption on white matter development and brain structure. This approach holds great promise in assessing neurotoxicity of xenobiotics in humans and wildlife.
Thyroid hormones play a critical role in brain development. EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis. This manuscript presents the results of magnetic resonance imaging (MRI) and volumetric analyses of the brains of offspring of dams exposed to the thyroid hormone synthesis inhibitor, propylthiouracil (PTU, 0, 3 and 10ppm) during gestation and lactation. The brains of offspring either 25 or 90 days of age exhibited a decrease in whole brain, gray matter and white matter volume. MRI images of the brains from the 10 ppm group reveal heterotopias within the corpus callosum that were confirmed in histological sections from the same brains. Illustrative examples of in vivo images ofthe brains of 90 day old rats demonstrated that such heterotopias are detectable in MRI images from live animals. This is the first study to detect PTU-induced heterotopias in live animals, demonstrating that MRI will be a valuable tool not only for their detection in toxicologic studies, but also to trace the origins and fate of heterotopias in the developing and maturing brain. MRI is a rapidly developing technique that will eventually play a significant role in characterizing the effects of toxicants in humans, experimental animals and wildlife. These findings demonstrate that MRI and volumetric analysis are excellent tools to examine the effects of thyroid hormone disruption on brain structure and myelination. They represent a significant step forward in the application of this technique to addressing significant issues in toxicology. Incorporation of MRI approaches may aid in our understanding of the neurotoxicity of several environmental pollutants that affect the thyroid system and thus possibly brain development in humans and wildlife populations (e.g., polychlorinated biphenyls (PCBs), brominated flame retardants (PBDEs), triclosan). The ability to detect WM reductions and brain structure abnormalities in rats that were caused by developmental TH disruption, but as adults show normal thyroid hormone levels, may be particularly relevant to epidemiological studies.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
TOXICOLOGY ASSESSMENT DIVISION