Citation:

Gilbert, M., R. Ford, S. Thomas, S. Spring, W. Oshiro, Pat Kosian, J. Ford, AND S. Degitz. Cortical Brain Malformation and Learning Impairments Induced by Developmental Thyroid Hormone Insufficiency: A Cross-Fostering Study. SOT, Baltimore, MD, March 12 - 16, 2017.

Impact/Purpose:

SOT presentation for development of Adverse Outcome Pathway for thyroid hormone disruption

Description:

Although it is clear that severe reductions in thyroid hormones (TH) during development alter brain structure and function, the impact of low level, timing, and duration of TH insufficiency is less well understood. We have previously reported the presence of a cortical heterotopia accompanied by learning deficits in adult rats exposed in utero and throughout lactation to the TH synthesis inhibitor 6-propylthiouracil (PTU). The present study was designed to determine whether exposure limited to the prenatal or postnatal period is sufficient, or if both are required for these neurotoxic outcomes. Pregnant rats were administered PTU via drinking water (0 or 3 ppm) from gestational day (GD) 6 to postnatal day (PN) 14. On PN2, half of the offspring from each control litter was cross fostered to a PTU-treated dam to nurse (CON-PTU); half of each PTU exposed litter was fostered to a control dam (PTU-CON). This scheme created four treatment groups: pups receiving PTU only prenatally (PTU-CON), only postnatally (CON-PTU), throughout development (PTU-PTU), or control only (CON-CON). Blood was sampled from dams during pregnancy, lactation and at weaning for TH and PTU analysis. Pups were sacrificed postnatally and in adulthood, with blood collected for TH and PTU measurements and brains collected for detection of a cortical heterotopia. Learning was assessed in adult male and female offspring using a trace fear conditioning paradigm. We show the permanent presence of a heterotopia in brains of both sexes in animals exposed to PTU prenatally (PTU-CON and PTU-PTU), but not in those receiving PTU only during the postnatal period (CON-PTU). In contrast, impairment in fear conditioning was limited to male offspring, and only observed in animals exposed throughout neurodevelopment (PTU-PTU). These findings indicate that cortical heterotopia formation requires TH insufficiency during the gestational period and that functional deficits appear independent of the presence of this cortical malformation. Does not reflect EPA policy

Record Details: