Office of Research and Development Publications

A transient window of hypothyroidism alters neural progenitor cells and results in abnormal brain development

Citation:

OShaughnessy, K., S. Thomas, S. Spring, J. Ford, R. Ford, AND M. Gilbert. A transient window of hypothyroidism alters neural progenitor cells and results in abnormal brain development. Scientific Reports. Nature Publishing Group, London, Uk, 9:4662, (2019). https://doi.org/10.1038/s41598-019-40249-7

Impact/Purpose:

It is well accepted that thyroid hormone (TH) disruption during pregnancy can induce severe intellectual disability in the developing child. However, it is not understood how less severe disturbances to the thyroid axis may affect neurodevelopment. This issue is of high importance given that many environmental contaminants, like pesticides perfluorinated compounds, alter serum TH concentrations in laboratory animals. To address these issues, this study evaluated the mechanistic basis in which a maternal goitrogen exposure alters brain development in rats. We show that five days of maternal goitrogen treatment (10 ppm propylthiouracil – pharmaceutical) during the perinatal period (GD19-PN2) is sufficient for birth defect formation in the pup brain. We next show transcriptional and structural changes of the brain, including abnormal cell adhesion and progenitor cell morphology. Interestingly, these acutely affected stem cells are at the intersection of the cerebrospinal fluid and vasculature, two sources of brain THs. These data indicate that acute TH disruption induces a cortical malformation, that may be caused by localized alterations of neural progenitor cells. This work highlights the spatiotemporal vulnerabilities of the developing brain, and suggests that maintenance of euthyroidism across pregnancy is critical to children’s health.

Description:

Cortical heterotopias are characterized as clusters of ectopic neurons in the brain, and are associated with neurodevelopmental disorders like epilepsy and learning disabilities in patients. We have previously characterized the robust penetrance of a heterotopia in a rat model, induced by thyroid hormone (TH) disruption during pregnancy. However, how maternal TH insufficiency results in this birth defect is unknown. Here we first determined the developmental window susceptible to endocrine disruption, and characterized a cellular mechanism likely contributing to heterotopia formation in rats. We show that five days of maternal goitrogen treatment (10 ppm propylthiouracil) during the perinatal period (GD19-PN2) is sufficient for heterotopia development. Beginning in the early postnatal brain, neurons begin to collect near the ventricular epithelium of treated offspring. We next show transcriptional and structural changes of this region, including abnormal cell adhesion and radial glia morphology. Interestingly, this affected cell population is juxtaposed to both the cerebrospinal fluid and vasculature, two sources of brain THs. These data indicate that acute TH disruption induces a cortical malformation, caused by localized alterations of neural progenitor cells. This work highlights the spatiotemporal vulnerabilities of the developing brain, and suggests that maintenance of euthyroidism across pregnancy is critical to children’s health.