Insufficient thyroid hormone (TH) during development results in permanent neurological deficits. These deficits are the result of perturbed TH-mediated brain development. Interestingly, insufficient insulin-like growth factor 1 (Igf-1) during development results in neurological deficits that are similar to those reported for developmental hypothyroidism. This observation suggests that deficits associated with low TH during development may be the result of altered Igf-1 expression in the developing brain. To test this, timed-pregnant mice were treated with thyroid gland inhibitors from gestational day 16 (GD16) until postnatal day 21 (P21) to induce a hypothyroid state. A parallel set of untreated timed-pregnant mice were used as controls. Brains from exposed and control pups were collected at P7, P14, P21, and P42 and processed for detecting Igf-1 mRNA by RNA isolation and reverse-transcriptase quantitative real-time PCR. Trunk blood was collected to measure serum thyroxin (T4) by ELISA. Body weights and total wet brain weights were also quantified. Developmentally hypothyroid mice weighed significantly less at all ages. Wet brain weights were significantly smaller in hypothyroid mice at P7, P21, and P42. Igf-1 mRNA levels did not differ significantly in the cortex compared to euthyroid controls. However, Igf-1 mRNA levels were significantly decreased in the hippocampus at P7, and in the cerebellum at P14. Interestingly, Igf-1 mRNA levels were increased in hypothyroid mice at P42 in the hippocampus. Because treatment of goitrogens ceased at P21, any differences seen at P42 are the result of permanent TH deficit during early development. Since this result was not reflected in decreased Igf-1 expression at P42 in any region, it can be assumed that TH has more complex mechanistic actions than just regulating Igf-1 gene expression. It is also safe propose brain Igf-1 mRNA expression is affected by low serum TH; yet the way Igf-1 gene expression is perturbed is regionally and temporally specific. These findings identify a novel, previously unconsidered, mechanism by which thyroid hormone insufficiency during development results in neurological deficits.
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Second Committee Member
Date of Degree
Master of Science (MS)
Science, Engineering and Technology
Graber-Feesl, Cari Lee, "Quantification of Brain-Region Specific Alterations in Insulin-Like Growth Factor-1 Expression During Developmental Hypothyroidism" (2017). All Theses, Dissertations, and Other Capstone Projects. 742.
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