Citation:

OShaughnessy, K., S. Thomas, Pat Kosian, S. Degitz, AND M. Gilbert. Transient Maternal Hypothyroidism Alters Neural Progenitor Expression Resulting in Abnormal Brain Development. SOT, Baltimore, MD, March 12 - 16, 2017.

Impact/Purpose:

Presentation at Society of Toxicology - Quantitative adverse outcome pathway (AOP) development requires mechanistic data for brain dysfunction associated with developmental hypothyroidism. These data will aid in the development of quantitative AOPs and interpretation of high throughput models of thyroid disruption for risk-based decision making.

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. 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. Our ongoing work has demonstrated that prenatal TH insufficiency is necessary for heterotopia formation (see Gilbert et al.); thus, 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 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 during these critical stages 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 neural progenitors. 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. Does not reflect EPA policy.

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