Reductions in Neocortical Parvalbumin Expression Due to Iodine Deficiency and Ammonium Perchlorate Exposure

Endocrine disrupting chemicals (EDCs) can  interfere with thyroid hormone (TH) production and action. Genetically modified mouse models of TH receptors, transporters, and metabolizing enzymes have revealed neurons expressing parvalbumin (Pvalb) are sensitive to TH disruptions. We sought to determine if more physiologically-relevant thyroid axis perturbations, induced by ID or the EDC perchlorate, would alter Pvalb expression in the developing brain. Female LE rats were maintained on either iodine replete or insufficient diets for > 4 weeks before breeding. Sperm-positive female rats were exposed to 0 or 300 ppm perchlorate in the drinking water beginning on gestational day 6. Perchlorate and ID independently reduced serum T4 by~35% in dams without significantly affecting offspring TH, whereas serum T4 in dams and pups was suppressed by~75% following combined exposures to ID and perchlorate. Immunohistochemistry for Pvalb was performed on postnatal day 14 pup brains (6-8 litters/group). Relative to control, no differences in Pvalb+ neuron number were evident in somatosensory or cingulate cortices in offspring of ID or perchlorate dams. However,  Pvalb+ neurons were reduced by~50% in both cortical regions when exposures were combined. These findings suggest that deficiency in Pvalb+ interneurons in the neonatal brain may represent a sensitive marker for EDCs. As Pvalb-expressing interneurons are critical to formation of neural networks, their disruption in the developing brain may contribute to neurological impairments accompanying TH insufficiency. These findings further reveal the presence of adverse neurodevelopmental consequences when a thyroid disrupting EDCs is presented under conditions of ID. Does not reflect EPA policy.

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. Alterations in parvalbumin expression in inhibitory neurons in the brain 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. In this report we demonstrate for the first time environmental chemical-induced reductions in the numbers of this set of 'pacemaker' neurons that control excitatory tone and the formation of neural netwoks in the developing brain. We further demonstrate that dietary insufficiencies can compound the effects of chemical exposure with implications for environmental justice. Further, they provide impetus to examine parvalbumin expression as a marker of neurodevelopmental thyroid disruption.

Citation

Hawks, M., K. Bell, R. Thomas, J. Ford, AND M. Gilbert. Reductions in Neocortical Parvalbumin Expression Due to Iodine Deficiency and Ammonium Perchlorate Exposure. Developmental Neurotoxicology Society (DNTS), Charleston, SC, June 24 - 28, 2023.