The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate's history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development.

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Biomarkers of Nutrition for Development (BOND)-Iron Review.

I. Cell Proliferation in Normal Thyroid Tissue In Vivo ............................................... A. Physiological situation ........................................................................... B. Growth under stimulatory conditions ........................................................... C. Coordination between various thyroid cell types ................................................ D. Stem cells ........................................................................................ II. Methodology and Model Systems for Study of Thyroid Growth ................................... A. Model systems ................................................................................... B. Methodology: indexes of cell proliferation ...................................................... C. Working definition: growth control ratio ........................................................ III. Differentiation, Determination, Differentiation Expression ....................................... A. Thyroid system .................................................................................. B. Model for thyroid ................................................................................ IV. Extracellular Signals Involved in Control of Proliferation of Thyroid Cells ....................... A. Thyrotropin ...................................................................................... B. Iodine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Other hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Pathological signals .............................................................................. E. Local signals ..................................................................................... V. Pathways Regulating Thyroid Cell Proliferation ................................................... A. General considerations .......................................................................... B. Mitogenic and differentiating action of thyrotropin ............................................ C. Effect of factors other than thyrotropin on proliferation and differentiation ................. D. Role of adenosine 3’,5’-cyclic monophosphate, phosphatidylinositol bisphosphate, and tyrosine protein kinase cascades in thyrocyte proliferation ......................................... E. Kinetics of biochemical events in various thyroid mitogenic pathways ........................ F. Role of autocrine loop ............................................................................ VI. Apparently Opposite Programs: Proliferation and Differentiation Expression Are Induced by Thyrotropin and Adenosine 3’,5’-Cyclic Monophosphate Cascade .............................. VII. Growth Control and Goitrogenesis .................................................................. A. General concepts ................................................................................. B. Graves’ disease ................................................................................... C. Congenital defects ............................................................................... D. Thyroid adenoma ................................................................................ E. Sporadic goiter ................................................................................... VIII. Hypothetical and Existing Examples of Constitutive Activation of Adenosine 3’,5’-Cyclic Monophosphate Cascade ........................................................................ A. Adenylate cyclase-coupled receptors ............................................................ B. Cyclase-activating guanosine triphosphate-binding protein .................................... C. Adenosine 3’,5’-cyclic monophosphate-dependent protein kinase ............................... D. Negative controls of adenosine 3’,5’-cyclic monophosphate cascade ............................. IX. Conclusions .......................................................................................... 667 667 668 668 669 669 669 670 671 671 671 672 673 673 674 674 674 674 675 675 676 677

Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors

This article reviews the thyroid system, mainly from a mammalian standpoint. However, the thyroid system is highly conserved among vertebrate species, so the general information on thyroid hormone production and feedback through the hypothalamic-pituitary-thyroid (HPT) axis should be considered for all vertebrates, while species-specific differences are highlighted in the individual articles. This background article begins by outlining the HPT axis with its components and functions. For example, it describes the thyroid gland, its structure and development, how thyroid hormones are synthesized and regulated, the role of iodine in thyroid hormone synthesis, and finally how the thyroid hormones are released from the thyroid gland. It then progresses to detail areas within the thyroid system where disruption could occur or is already known to occur. It describes how thyroid hormone is transported in the serum and into the tissues on a cellular level, and how thyroid hormone is metabolized. There is an in-depth description of the alpha and beta thyroid hormone receptors and their functions, including how they are regulated, and what has been learned from the receptor knockout mouse models. The nongenomic actions of thyroid hormone are also described, such as in glucose uptake, mitochondrial effects, and its role in actin polymerization and vesicular recycling. The article discusses the concept of compensation within the HPT axis and how this fits into the paradigms that exist in thyroid toxicology/endocrinology. There is a section on thyroid hormone and its role in mammalian development: specifically, how it affects brain development when there is disruption to the maternal, the fetal, the newborn (congenital), or the infant thyroid system. Thyroid function during pregnancy is critical to normal development of the fetus, and several spontaneous mutant mouse lines are described that provide research tools to understand the mechanisms of thyroid hormone during mammalian brain development. Overall this article provides a basic understanding of the thyroid system and its components. The complexity of the thyroid system is clearly demonstrated, as are new areas of research on thyroid hormone physiology and thyroid hormone action developing within the field of thyroid endocrinology. This review provides the background necessary to review the current assays and endpoints described in the following articles for rodents, fishes, amphibians, and birds.

General Background on the Hypothalamic-Pituitary-Thyroid (HPT) Axis

The purpose of this review is to summarize current knowledge of the etiology of euthyroid and toxic multinodular goiter (MNG) with respect to the epidemiology, clinical characteristics, and molecular pathology. In reconstructing the line of events from early thyroid hyperplasia to MNG we will argue the predominant neoplastic character of nodular structures, the nature of known somatic mutations, and the importance of mutagenesis. Furthermore, we outline direct and indirect consequences of these somatic mutations for thyroid pathophysiology and summarize information concerning a possible genetic background of euthyroid goiter. Finally, we discuss uncertainties and open questions in differential diagnosis and therapy of euthyroid and toxic MNG.

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Molecular pathogenesis of euthyroid and toxic multinodular goiter.

Thyroid hormones play an important role in brain development, but the mechanism(s) by which triiodothyronine (T3) mediates neuronal differentiation is poorly understood. Here we demonstrate that T3 regulates the neurotrophic factor, neurotrophin-3 (NT-3), in developing rat cerebellar granule cells both in cell culture and in vivo. In situ hybridization experiments showed that developing Purkinje cells do not express NT-3 mRNA but do express trkC, the putative neuronal receptor for NT-3. Addition of recombinant NT-3 to cerebellar cultures from embryonic rat brain induces hypertrophy and neurite sprouting of Purkinje cells, and upregulates the mRNA encoding the calcium-binding protein, calbindin-28 kD. The present study demonstrates a novel interaction between cerebellar granule neurons and developing Purkinje cells in which NT-3 induced by T3 in the granule cells promotes Purkinje cell differentiation.

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Neurotrophin-3 induced by tri-iodothyronine in cerebellar granule cells promotes Purkinje cell differentiation.

Goitre growth was investigated in rats receiving a low iodine diet (less than 0.1 microgram iodine/g) and either 1 g/l KClO4 or 1 g/l propylthiouracil (PTU), or a combination of KClO4 or PTU with 50.82 nmol/1 T3 in tap water for 3 weeks. To investigate goitre involution, rats with iodine-deficient goitres were treated for 3 weeks either with T3 (0.5 microgram T3/day = 0.768 nmol/day), iodide (0.5 or 2.7 micrograms KI/day) or a combination of T3 with both iodide doses. Histology together with total DNA distinguished between hypertrophy and hyperplasia of the gland. During goitre growth there was highly significant correlation between goitre weight and TSH serum level (r = 0.93, P less than 0.001). Thyroid total DNA, however, was only weakly correlated to TSH but was inversely related to the degree of iodine deficiency. During goitre regression, TSH levels were normalized, histological signs of hypertrophy had disappeared, and thyroid weight was nearly normalized in all therapy groups. Total DNA, however, was normalized only with 2.7 micrograms KI/day (95 +/- 18 micrograms DNA/gland), and still elevated in all other groups. The highest DNA levels were found under T3 therapy (143 +/- 21 micrograms DNA/gland) and under 0.5 microgram KI/day (161 +/- 19 micrograms DNA/gland). Reduction of total DNA was independent of TSH, but followed replenishment of the iodine content of the glands. We conclude that TSH mainly induces hypertrophy, whereas thyroid hyperplasia is mainly regulated by the intracellular iodine content.

K. Gropper

Papers

Hypertrophy and hyperplasia during goitre growth and involution in rats--separate bioeffects of TSH and iodine.

Effect of iodide versus T3 on hypertrophy and hyperplasia in iodine-deficient rat goiter