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Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose-response model
Fisher, J., S. Li, K. Crofton, R. Zoeller, E. McLanahan, A. Lumen, AND M. Gilbert. Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose-response model. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 132(1):75-86, (2013).
It is well established that adequate levels of thyroid hormone (TN) are essential for normal brain development. Xenobiotic-induced changes in the hypothalamic-pituitary thyroid (HPT) axis in rodents, using common measurements, such as serum TH and thyroid stimulating hormone (TSH), are difficult to interpret for human health significance. A description of changes in serum TH is pivotal in extrapolating effects observed in animals to humans because both TN and TSH are widely used biomarkers of HPT axis status. Biologically-based dose response (BBDR) models for the HPT axis are computational tools that can assist in dose response analysis for thyroid active chemicals in laboratory animals and in extrapolation of rodent HPT perturbations to humans. Such an approach also provides a place from which to begin to define the relationships between serum TH and adverse outcomes. In a companion paper (Gilbert et al., An Animal Model of Marginal Iodine Deficiency During Development: The Thyroid Axis and Neurodevelopmental Outcome), basic parameters of thyroid function were reported for a range of dietary iodine deficiencies. The present paper utilizes these data to construct a BBDR model for the lactating dam and nursing pup. A BBDR-HPT axis model calibrated using key data sets collected from a single project is favorable to gathering data from many diverse experiments spanning 3-4 decades. The strength of having information over several levels of iodide intake with a full characterization of serum TH perturbations collected by a single laboratory allowed for an informative quantitative analysis of the HPT axis. The model provides an analysis of the ‘stress’ of iodide deficiency on the rats HPT axis as it tries to maintain a euthyroid state. The impact of both papers together is that we show for the first time, a correlation between graded responses to iodide deficiency, modest changes in serum T4 and irreversible effects on nervous system function. The BBDR-HPT axis model described in the lactating rat and pup is useful in predicting alterations in the HPT axis caused by iodide deficiency, and with modifications this model could be extended to study thyroid active chemicals or drugs that perturb the thyroid axis by other means. Furthermore extending the model in both directions, upstream to describe cellular and molecular events, associated with TH status and downstream to tie alterations in HPT axis status to disruptions in brain developmental processes as was performed by Gilbert et al. (companion paper), will reduce the uncertainty in using serum TH levels as a proxy for HPT axis induced developmental neurotoxicity. With the continued growth of computational tools in toxicology, quantitative descriptions of signaling pathways, such as those involved in the HPT axis, will be forthcoming. Incorporation of such information in a BBDR framework will provide a more accurate depiction of the HPT axis signaling pathways and a higher fidelity model to represent this complex biological system.
A biologically-based dose response (BBDR) model for the hypothalamic-pituitary thyroid (BPT) axis in the lactating rat and nursing pup was developed to describe the perturbations caused by iodide deficiency on the HPT axis. Model calibrations, carried out by adjusting key model parameters, were used as a technique to evaluate HPT axis adaptations to dietary iodide intake in euthyroid (4.1 -39 ug iodide/d) and iodide deficient (0.31 and 1.2 ug iodide/d) conditions. Iodide deficient conditions in both the dam and pup were described with increased blood flow to the thyroid gland, TSH-mediated increase in thyroidal uptake of iodide and binding of iodide in the thyroid gland (organification), and in general, reduced thyroid hormone production and metabolism. Alterations in thyroxine (T4) homeostasis were more apparent than for triiodothyronine (T3). Model-predicted average daily area-under-the-serum-concentration-curve (AUC, nM*day) values for T4 at steady-state in the dam and pup decreased by 14-15% for the 1.2 ug iodide /d iodide deficient diet and 42 to 52% for the 0.31 ug iodide /d iodide deficient diet. In rat pups that were iodide deficient during gestation and lactation, these decreases in serum T4 levels were associated with declines in thyroid hormone in the fetal brain and a suppression of synaptic responses in the hippocampal region of the brain of the adult offspring (Gilbert et al., 2012).