Citation:

OShaughnessy, K., S. Thomas, J. Ford, R. Ford, AND M. Gilbert. Transient Maternal Hypothyroidism Alters Neural Progenitors Resulting in Abnormal Brain Development. Developmental Neurotoxicology Society (DNTS), Denver, Colorado, June 24 - 29, 2017.

Impact/Purpose:

This work will be used to understand mechanisms underlying brain malformations induced by thyroid hormone disruption. It represents a step to build an AOP for thyroid disruption and neurodevelopmental disorders..

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, epilepsy, and learning disabilities. 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. This structural abnormality is highly reproducible, and its severity is dose-dependent; however, little is known about the cellular and molecular alterations that link decreased TH to this phenotype. To elucidate the mechanisms of this adverse development we first determined the precise period of TH sensitivity. Our ongoing work has demonstrated that prenatal TH insufficiency is necessary for heterotopia formation. Therefore, 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 addition to serum and brain TH levels across multiple developmental stages. We show that five days of PTU treatment during the perinatal period (GD19-PN2) is both sufficient and necessary for heterotopia formation. Beginning in the early postnatal brain, we find that mature neurons begin to collect in the periventricular space of treated animals. Quantitative gene expression analyses of this region show significant changes in a suite of genes, including downregulation of Spred1, a negative regulator of Ras–MAPK–ERK signaling. Others have shown that transient downregulation of Spred1 in the mouse brain results in a heterotopia by increasing stem cell self-renewal and progenitor proliferation in the ventricular zone. Consistent with these findings, we also see upregulation of Pax6, a marker of radial glial progenitors. We then show abnormalities in radial glial morphology and organization within the hypothyroid brain, which suggests that abnormal cell migration may underlie heterotopia formation. These data indicate that acute TH disruption induces a cortical malformation, and provides a potential functional role between hypothyroidism and dysregulation of neural progenitors in the developing brain. Work does not reflect EPA policy.

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