Citation:

GILBERT, M. E., J. GOODMAN, S. THOMAS, AND S. PHANI. NEURONS COMPRISING A HETEROTOPIA INDUCED BY DEVELOPMENTAL HYPOTHYROIDISM ARE BORN LATE IN GESTATION. Presented at Society for Neuroscience, Washington, DC, November 12 - 16, 2005.

Description:

We previously described an abnormal cluster of neurons, a heterotopia, located in the corpus callosum in rat pups born to dams exposed to the goitrogen, propylthiouracil (PTU, Goodman et al., SfN 2004). In this study we determined 1) whether the formation of the heterotopia was unique to hypothyroidism induced by PTU and 2) the birth date of the cells within the heterotopia. Pregnant LE rats were exposed to methimazole (MMI, 200 ppm) or PTU (10 ppm) in drinking water from gestational day (GD) 6 to postnatal day (PN) 30. Offspring were perfused with 4% paraformaldehyde (PAF) on PN23 and PN86 and the brains prepared for histological analysis. Heterotopias were present in all pups examined from PTU and MMI dams. The bulk of the cells within the heterotopia were of a neuronal phenotype. The birth date of cells within the heterotopia was determined by exposing pregnant dams to 0, 1, 3 or 10 ppm PTU from GD 6-PN30. Dams from each dose group also received 50 mg/kg of bromodeoxyuracil (BrdU), ip, once daily from GD 14-16 or GD 17-19. Pups were sacrificed on PN4, 10, 23 and 86, brains were fixed in 4% PAF, and tissue processed for BrdU immunostaining. A heterotopia was never observed in controls, but was present in all animals exposed to 3 and 10 ppm, and 50% of animals from the 1 ppm dose group. Many BrdU-positive cells were present in the heterotopia of offspring of dams injected between GD17-19 but were absent in the heterotopia of offspring from dams injected on GD14-16. These results confirm that this cortical malformation is induced by thyroid hormone insufficiency. Cells within the heterotopia are born late in gestation and may have been destined for cortex or hippocampus. We postulate that some developmental disorders of childhood origin stemming from altered cell migration may derive from early thyroid hormone insufficiency. Does not reflect EPA policy NEURONS COMPRISING A HETEROTOPIA INDUCED BY DEVELOPMENTAL HYPOTHYROIDISM ARE BORN LATE IN GESTATION. M.E. Gilbert1*, S. Thomas2, S. Phani2, J.H. Goodman2. Neurotoxicology Div, 1US EPA, RTP, NC, USA, 2CNRRR, Helen Hayes Hosp, W. Haverstraw, NY, USA We have previously reported an abnormal cluster of neurons located in the corpus callosum in rat pups born to dams exposed to the goitrogen, propylthiouracil (PTU) (Goodman et al., SfN, 2004). In this study we determined 1) the specificity of the formation of the heterotopia to hypothyroidism induced by PTU and 2) the birthdate of the cells within it. Pregnant LE rats were exposed to methimazole (MMI, 200 ppm) or PTU (10 ppm) in drinking water from gestational day (GD) 6 to postnatal (PN) 30. Offspring were perfused with 4% paraformaldehyde on PN23 and PN86 and brains prepared for histological analysis. Heterotopia were present in all pups examined from PTU and MMI dams. The birthdate of cells within the heterotopia was determined by exposing pregnant dams to 0, 1, 3 or 10 ppm PTU from GD 6-PN30. Dams from each dose group were also administered 50 mg/kg of bromodeoxythiouracil (BrdU), ip, once daily from GD 14-16. A second group received BrdU from GD 17-19. Pups were sacrificed on PN4, 10, 23 and 86, brains were fixed in 4% paraformaldehyde, and tissue processed for BrdU immunostaining. A heterotopia was never observed in controls, was present in all animals from the 3 and 10 ppm dose groups, and 50% of animals from the 1 ppm dose group. BrdU-positive cells were not present in the heterotopia of offspring of dams injected between GD14-16. Many BrdU positive cells were observed in the heterotopia of offspring from dams of the GD17-19 group. The results confirm that this cortical malformation is induced by thyroid hormone insufficiency and that cells within the heterotopia are born late in gestation and may have been destined for cortex or hippocampus. We postulate that developmental disorders of childhood origin stemming from altered cell migration may derive from early thyroid hormone insufficiency. Does not reflect EPA policy

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