Thyroid Hormone Insufficiency and the Developing Brain – Iodine Status Exacerbates Neurological Consequences of Environmental Chemical Exposure

Although rodent models of severe TH deficiency have been crucial for improving our understanding of the interdependence of thyroid hormone and brain development, the impact of thyroid dysfunction induced by environmental contaminants is much more subtle. Reliance of phenotypes identified in rodent models following treatment with high doses of hormone synthesis inhibitors like methimazole and propylthiouracil are too insensitive to detect interference with thyroid signaling induced by environmental contaminants. Iodine is an essential element required for thyroid hormone synthesis and maintaining iodine status is especially important during pregnancy for the developing fetal brain. Perchlorate is a drinking water contaminant that interferes with iodine uptake and reduces hormone production. Perchlorate’s action to block the sodium-iodine symporter has raised concern that the progeny of pregnant women with insufficient dietary iodine may be particularly susceptible to neurological insult from perchlorate exposure. This presentation examines the developmental effects of perchlorate and iodine deficiency on a number of neurological outcomes in a rat model. Both treatments dose-dependently impaired synaptic transmission in the hippocampus, yet neither had effects on standard behavioral measures of learning and sensory processing. However, when perchlorate was combined with iodine deficiency, structural defects in brain were produced and neurobehavioral outcomes revealed. Reductions in serum hormones in the dam, fetus and neonate that persist to the first week of life were required to induce morphological changes in brain. Serum hormone declines were accompanied by deficits in brain hormone concentrations, and expression of thyroid-hormone-responsive genes. It appears that the neurodevelopmental effects of perchlorate exposure are not only unmasked but greatly exacerbated under conditions of dietary iodine insufficiency, effects that would not necessarily be predicted from rodent models of either one alone. These findings also underscore the importance of recognizing species differences in both the timing of brain development and kinetics of exposure that may increase the vulnerability of the human fetal brain. Does not reflect EPA policy

Impact/Purpose

Quantitative adverse outcome pathways (qAOPs) are under needed to improve predictions of neurodevelopmental consequences that result from thyroid disruption. Combined effects of thyroid perturbation from insults from different points along the thyroid axis are described as AOP networks. Thyroid hormones (TH) are critical for brain development and iodine is a critical element for thyroid hormone synthesis. Perchlorate is an environmental contaminant that reduces access of iodine to the thyroid gland and thereby interferes with thyroid hormone synthesis. This work was conducted to ascertain the combined effects iodine deficiency with perchlorate exposure on thyroid-dependent neurodevelopmental consequences at the hormonal, molecular, cell signaling, anatomical and behavioral ends of the AOP continuum. The data presented here detail the dose-dependent serum and brain hormone effects of marginal iodine insufficiency and perchlorate exposure during pregnancy in a rodent model and their effects on a battery of assessments of neurodevelopmental outcomes. These are contrasted with the much more devastating effects of combining low dietary iodine with a modest dose of perchlorate. These provide quantitative data for critical upstream key events to improve predictions of adverse outcomes of developmental neurotoxicity induced by thyroid hormone disruption. The finding also underscore the importance of recognizing species differences in both the timing of brain development, dosimetry, kinetics that will influence the extrapolation of observations in rodents to predictions of fetal brain development in humans.

Citation

Gilbert, Mary E. Thyroid Hormone Insufficiency and the Developing Brain – Iodine Status Exacerbates Neurological Consequences of Environmental Chemical Exposure. Endocrine Society-Virtual, NA, Virtual, March 23 - 30, 2021.