Using biologically motivated models for the lactating mother and nursing infant to link iodine deficiency with thyroid hormone production and hypothyroxinemia

摘要

Iodine is an essential micronutrient for thyroid hormone formation and is obtained primarily from food. Iodine deficiency remains a public health issue world-wide despite ongoing interventions. Iodide deficiency during development may lead to irreversible neurodevelopmental toxicity. The nursing infant is recognized as a sensitive subpopulation; however, no quantitative analyses of the relationship between intake of iodide and thyroid hormone homeostasis has been published for the nursing infant and lactating mother. A biologically motivated model was developed to examine the effect of iodine sufficiency and moderate insufficiency on thyroid hormone serum levels in the nursing infant and lactating mother pair. The mechanism of action for iodide insufficiency induced hypothyroxinemia was assumed to be a reduction in thyroid hormone production caused by reduced organified iodine content of the thyroid gland. Hypothyroxinemia is defined as low serum free thyroxine (fT4), while serum thyroid stimulating hormone (TSH) remains normal. Maternal hypothyroxinemia during early pregnancy is associated with neurological deficits in children. The adverse consequences of hypothyroxinemia in infants and neonates are less clear. Using published statistically-derived population reference ranges for serum TSH, free fT4, and total thyroxine (tT4) in the nursing infant, simulations were conducted for dietary iodine intake ranging from moderately low (50-100 μg/day) to sufficient (290 to 400 ug/day). Development and calibration of the models clearly established that the infant hypothalamic pituitary thyroid (HPT) axis is 'revved up' and through-put is much greater than in the adult. Interestingly, non-TSH compensatory mechanisms, may be involved in maintaining serum thyroid hormones for conditions of chronic intake of low dietary iodide, and are not well understood. Simulation of data sets from intervention studies, where iodine is added to the diet of iodine deficient populations of lactating mothers, suggests that the utilization of the iodine by the HPT is less than would be predicted for an iodine sufficient population. The reasons for these findings are unknown; however, the model was used to help interpret these data. This biologically motivated model can be linked to PBPK models for thyroid active chemicals or drugs that act on the HPT axis within the thyroid gland or elsewhere in the body such as the brain or organs involved in deiodinase metabolism or Phase II conjugation of thyroid hormones. Understanding the iodine- HPT axis status is fundamental to interpreting the effects of chemicals or drugs on the HPT axis.