Citation:

OShaughnessy, K., S. Thomas, J. Ford, R. Ford, AND M. Gilbert. Transient Maternal Hypothyroidism Alters Neural Progenitor Cells Resulting in Abnormal Brain Development. NC SOT, RTP, NC, October 30, 2017.

Impact/Purpose:

Presentation for NC Society of Toxicology - Submission for PARC Award - Extended Abstract

Description:

Heterotopias are a birth defect of the brain and have varying etiologies in humans. They are characterized as clusters of mislocalized neurons and are associated with disorders such as autism and epilepsy. We have previously characterized the robust penetrance of a cortical heterotopia in a rat model, induced by low/moderate levels of thyroid hormone (TH) disruption during neurodevelopment (Fig. 1). Because of the reproducible and dose-dependent nature of this defect, it represents an ideal anatomical abnormality to build a quantitative adverse outcome pathway (qAOP). However, little is known about the cellular and molecular mechanisms that link decreased TH to this adverse phenotype. To elucidate these key events, we first determined the precise period of TH sensitivity. First, we treated pregnant rats with a moderate dose (10 ppm) of propylthiouracil (PTU) to induce hypothyroidism at four distinct gestational windows. The presence and size of the heterotopia was quantified in the offspring, in addition to serum and brain TH levels across multiple developmental stages. We show that five days of goitrogen treatment during the perinatal period (GD19-PN2) is both sufficient and necessary for heterotopia formation (Fig. 2A-D). Beginning in the early postnatal brain, mature neurons begin to collect in the periventricular area of the treated animals (Fig. 3A). Quantitative gene expression analyses during these stages show significant changes in a suite of genes, including downregulation of Spred1, a regulator of Ras–MAPK–ERK signaling (Fig. 3B). Others have shown that transient downregulation of Spred1 in the mouse brain results in a heterotopia by altering stem cell renewal and progenitor cell structure in the ventricular zone. Consistent with these findings, we also see upregulation of Pax6, a marker of neural progenitors that aide in cell migration during development (radial glial cells, Fig. 3B’). Morphologically, radial glial cells in hypothyroid animal are also altered, suggesting that cell migration may underlie heterotopia formation (Fig. 3C). These data indicate that acute TH disruption induces a cortical malformation, and suggest a functional role between hypothyroidism and dysregulation of neural progenitors in the developing brain. These results will be used in qAOP development, and in interpretation of high throughput models of neurodevelopment for risk-based decision-making. This work does not reflect EPA policy.

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