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Iodothyronine Levels in the Human Developing Brain: Major Regulatory Roles of Iodothyronine Deiodinases in Different Areas

Department of Internal Medicine (M.H.A.K., D.M., T.J.V.), Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands; Departmento de Endocrinología (R.M.d.M., M.J.O., G.M.d.E.), Instituto de Investigaciones Biomédicas Albert Sols, Consejo Superior de Investigaciones Cientificas-UAM, 28029 Madrid, Spain; Pathology Department (A.H.), Royal Hospital for Sick Children, Yorkhill National Health Service Trust, Glasgow G3 8SJ, Scotland, United Kingdom; and Maternal and Child Health Sciences (R.H.), University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Theo J. Visser, Department of Internal Medicine, Erasmus Medical Center, Room Ee 502, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: t.j.visser{at}erasmusmc.nl.

Thyroid hormones are required for human brain development, but data on local regulation are limited. We describe the ontogenic changes in T₄, T₃, and rT₃ and in the activities of the types I, II, and III iodothyronine deiodinases (D1, D2, and D3) in different brain regions in normal fetuses (13–20 wk postmenstrual age) and premature infants (24–42 wk postmenstrual age). D1 activity was undetectable.

The developmental changes in the concentrations of the iodothyronines and D2 and D3 activities showed spatial and temporal specificity but with divergence in the cerebral cortex and cerebellum. T₃ increased in the cortex between 13 and 20 wk to levels higher than adults, unexpected given the low circulating T₃. Considerable D2 activity was found in the cortex, which correlated positively with T₄ (r = 0.65). Cortex D3 activity was very low, as was D3 activity in germinal eminence and choroid plexus. In contrast, cerebellar T₃ was very low and increased only after midgestation. Cerebellum D3 activities were the highest (64 fmol/min·mg) of the regions studied, decreasing after midgestation. Other regions with high D3 activities (midbrain, basal ganglia, brain stem, spinal cord, hippocampus) also had low T₃ until D3 started decreasing after midgestation. D3 was correlated with T₃ (r = –0.682) and rT₃/T₃ (r = 0.812) and rT₃/T₄ (r = 0.889).

Our data support the hypothesis that T₃ is required by the human cerebral cortex before midgestation, when mother is the only source of T₄. D2 and D3 play important roles in the local bioavailability of T₃. T₃ is produced from T₄ by D2, and D3 protects brain regions from excessive T₃ until differentiation is required.

This work was supported by European Community Grant QLG-2000-00930, Netherlands Organization for Scientific Research Grant 903-40-204, Fondo de Investigacion Sanitaria RCMN (C03/08) from Inst de Salud Carlos III, Chief Scientists Office Scottish Executive (K/MRS/50/C741), and Tenovus Scotland/Leng Trust.

Abbreviations: BG, Basal ganglia; BS, brain stem; Cbl, cerebellum; CC, cerebral cortex; CP, choroid plexus; D1, D2, D3, types I, II, and III deiodinase; DTT, dithiothreitol; GE, germinal eminence; H, hippocampus; MB, midbrain; PMA, postmenstrual age; PTU, 6-n-propyl-2-thiouracil; SC, spinal cord.

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