Citation:

Gilbert, M., K. Bell, M. Hawks, AND J. Ford. Impaired Inhibitory Hippocampal Network Function in Adult Rats Exposed Developmentally to Perchlorate and Dietary Iodine Deficiency. Society of Toxicology, Nashville, TN, March 19 - 23, 2023.

Impact/Purpose:

This work was conducted to provide quantitative information for the refinement of Adverse Outcome Pathways for thyroid disrupting chemicals and their potential impact on developing brain. In this report we demonstrate increased vulnerability of developing fetal brain to the exposure of a thyroid hormone disrupting chemical under conditions of dietary iodine deficiency. Evidence of persistent deficits in neural network functionality in adult offspring of exposed dams is demonstrated electrophysiologically in the intact animal. These impairments in synaptic transmission that persist to adulthood are foreshadowed by a decrease in the number of a subset of inhibitory interneurons in the neonatal brain that express the calcium binding protein, parvalbumin. The presence of this protein confers a pattern of electrical activity to these neurons that is unique among interneurons and is critical for synchronizing the excitatory output of neurons in developing neural circuits. Alterations in parvalbumin expression is emerging as a common outcome in chemically-induced thyroid disruption in rat, thyroid receptor mouse mutants, deiodinase and hormone transporter knock-out models, and in humans with mutations of the brain TH transporter, MCT8. Together, these data demonstrate that dietary insufficiencies can compound the effects of chemical exposure on neural function, with implications for environmental justice. Further, they provide impetus to examine parvalbumin expression as a marker of neurodevelopmental thyroid disruption.

Description:

Adequate supplies of iodine are essential for production of thyroid hormones (TH) with severe deficiencies leading to hypothyroidism. As TH are necessary for brain development, maintaining iodine status is especially critical during pregnancy. Perchlorate is an environmental contaminant that interferes with the transport of iodine into the thyroid gland and reduces TH synthesis.  As such, the offspring of pregnant women with iodine deficiency (ID) may be particularly susceptible to perchlorate exposure, with deleterious consequences on brain development. In a rat model, we have previously reported that developmental ID or perchlorate disrupts synaptic function in the hippocampus, impairing excitatory synaptic transmission but leaving functionality of inhibitory networks and synaptic plasticity intact. In this study, we investigated if the synaptic impairments induced by developmental perchlorate or marginal ID could be exacerbated if both treatments were delivered together.  Naïve female rats were maintained on either an iodine-replete (Control) or ID diet for a minimum of 4 wks, a regimen that reduced serum T4 by ~35%. Animals were bred and on gestational day 6, half of each group was exposed to 0 or 300 ppm perchlorate in the drinking water. Serum T4 in newborn pups was not altered by perchlorate, and was only transiently reduced by ID, recovering to control levels by PN6. In contrast, decreases in serum T4 >80% were evident in offspring of dams exposed to both ID and perchlorate on the day of birth, deficits that persisted throughout the neonatal period. As adults, under urethane anesthesia, electrodes were positioned stereotaxically in brains of male offspring to record field potentials in the hippocampus. Pairs of stimulus pulses at varying intervals were delivered to the perforant path, the ratio of the 1st and 2nd response recorded in the dentate gyrus reflecting the activity of GABAergic inhibitory interneurons. We observed a reduction in inhibitory output in animals born to ID dams exposed to perchlorate, with no difference from controls in groups exposed to ID or perchlorate alone. The electrophysiological impairments were accompanied by a decrease in the number parvalbumin (PV)-expressing cells in the cortex of pups on PN14. PV is a Ca-binding protein whose expression is limited to a subset of inhibitory interneurons, disruption of which is emerging as a common outcome in chemically-induced thyroid disruption in rat, thyroid receptor mouse mutants, deiodinase and hormone transporter knock-out models, and in humans with mutations of the brain TH transporter, MCT8. Together, these data demonstrate that ID can compound the effects of chemical exposure on neural function. Further, they provide impetus to examine PV expression as a marker of neurodevelopmental thyroid disruption.  Does not reflect EPA policy.

Record Details: