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The Effect of Maternal Hypothyroidism in the Fetal Brain Development

The Effect of Maternal Hypothyroidism in the Fetal Brain Development. Alexis Torres Endocrinology Presentation April 26, 2001. Anatomy and Mechanisms of Thyroid Hormones. Thyroid Gland In the trachea below the larynx Stimulator – TRH  TSH  T 4 , T 3 Thyroid Hormones Iodine dependent

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The Effect of Maternal Hypothyroidism in the Fetal Brain Development

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  1. The Effect of Maternal Hypothyroidism in the Fetal Brain Development Alexis Torres Endocrinology Presentation April 26, 2001

  2. Anatomy and Mechanisms of Thyroid Hormones • Thyroid Gland • In the trachea below the larynx • Stimulator – TRH  TSH  T4,T3 • Thyroid Hormones • Iodine dependent • T4, T3, rT3 • 5’-Monodeiodinase convert T4 T3 • Ligand-dependent transcription factors

  3. Actions and Pathology • Actions of Thyroid Hormones • Brain development (Neuronal differentiation) • Control basal metabolic rate • Growth – bone development •  Heart rate and myocardial contractility • Pathology Conditions • Thyroiditis • Hyperthyroidism -  T4, T3 • Hypothyroidism -  T4, T3 • Maternal Hypothyroidism

  4. Maternal Hypothyroidism • Deficiency in Thyroid Hormones • Affect expression of neuroendocrine specific protein • NSP-A, NSP-C • Promote fetal brain impairment

  5. Neuroendocrine Specific Protein (NSP) • Neural Differentiation • Thyroid Hormones mediator • NSP-A transcript - 3.5kb • NSP-C transcript - 1.5kb

  6. Objectives • Identify the effects of the absences of Thyroid Hormones in fetal brain development (Maternal Hypothyroidism) • Identify the timing of Thyroid Hormones effects • Speculate the mechanism by which Thyroid Hormones exerts their effects

  7. Experiment #1 Female rats treated with MMI and then mated (G1) MMI treated and MMI not treated injected with T4 (G14, G15) Day G16 dams were killed RIA was perform Fetus were removed from uterus In situ hybridization of fetus brain tissues NSP-A mRNA probe NSP-C mRNA probe Experiment #2 Pregnant rats treated with PTU (G1) PTU treated and PTU not treated injected with T4 or saline water (G15) Day G16 dams were killed RIA was perform Fetus were removed from uterus In situ hybridization of fetus brain tissues NSP-A mRNA probe NSP-C mRNA probe Materials and Methods

  8. Results • MMI treated dams • RIA •  T4 •  T3 •  TSH • PTU treated dams • RIA •  T4 •  T3 •  TSH

  9. MMI treated dams • After T4 injection • Normalized serum T3 • Normalized serum T4 •  serum TSH • PTU treated dams • After T4 injection •  T3 •  T4 •  TSH

  10. Effects of MMI treatment and T4 injection on NSP-A • Quantitative Analysis of autoradiograms films after In situ hybridization of NSP-A in G16 fetus •  NSP-A expression in fetal cortex

  11. Effects of MMI treatment and T4 injection on NSP-C • Quantitative Analysis of autoradiograms films after In situ hybridization of NSP-C in G16 fetus • Did not affect NSP-C expression

  12. Effects of PTU treatment and T4 injection on NSP-A • Quantitative Analysis of autoradiograms films after In situ hybridization of NSP-A in G16 fetus •  NSP-A expression in fetal cortex

  13. Distribution of NSP-A and NSP-C mRNAs during development in the euthyroid rat • On G15 both transcripts were detected •  progressively through P19 • On G16 transcripts were expressed in different parts of the cortex • NSP-A, proliferative ventricular zone and cerebellar Purkinje cells • NSP-C, outer and intermediate zone of the cortex and granular cells, absent from Purkinje cells • NSP-A and NSP-C in nasal epithelium, olphatory bulb

  14. Thyroid Hormone Regulates NSP-A mRNA in G16 Cortex

  15. Discussion and Conclusion • NSP-A expression is localizes in the proliferative zone of fetal cortex • Maternal Hypothyroidism selectively alters expression of NSP-A in this epithelium • Thyroid Hormones – responsive NSP-A is selectively expressed in cerebellar Purkinje cells affecting the motor deficits associated with neonatal hypothyroidism

  16. NSP-A expression was affected by the two treatments to the same extent: • Before conception • After conception • This may indicate that hypothyroidism before and during pregnancy those affect the course of fetal brain development

  17. Cytoplasm Fetus neuroblast T4 5’ M D T3 R T3 TRE R Gene X T3 NSP-A mRNA Nucleus X NSP-A Protein Maternal System Possible Indirect Mechanism

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