Citation:

Gilbert, M. AND A. Johnstone. A structural abnormality associated with graded levels of thyroid hormone insufficiency: Dose dependent increases in heterotopia volume. Presented at Neurobehavioral Teratology Society Meeting (NBTS), Tucson, AZ, June 22 - 26, 2013.

Impact/Purpose:

This abstract will be presented at the Neurobehavorial Teratology Society (NBTS) Meeting, part of the Society of Teratology Meeting, June 22-26-2013, Tucson, AZ

Description:

A large number of environmental contaminants reduce circulating levels of thyroid hormone (TH), but clear markers of neurological insult associated with modest TH insufficiency are lacking. We have previously identified the presence of an abnormal cluster of misplaced neurons in the corpus callosum (CC), a heterotopia, in adult rats following hypothyroidism induced by the hormone synthesis inhibitor, propylthiouracil (PTU). In this report we have investigated the dose- response relationships to administered dose of PTU, the magnitude of reductions in circulating TH, and the incidence and volume of the heterotopia in adult offspring of PTU-treated dams. Pregnant rat dams were administered 0, 1, 2, 3 or 10 ppm of PTU in the drinking water from gestational day 6 until pups were weaned on postnatal day 21 (PN2 1). Serum hormones in the dams were reduced in a dose-dependent manner, but at the lower dose levels (1, 2 and 3ppm) reductions were limited to T4 with no change in serum T3. At higher PTU concentrations, serum T3 was reduced in dams (1 Oppm) and pups on PN14 and 21 (3 and 10 ppm). All hormone levels returned to control levels in adulthood. On PN 130, female offspring were perfused with paraformaldehyde and sections prepared for immunohistochemistry for the neuron-specific antibody NeuN. All sections (40-45 50u through the hippocampus) were examined for the presence of a heterotopia in the CC. A dose-dependent increase in incidence and volume of heterotopic region was observed as the level of TH insufficiency increased. The heterotopia in the two highest dose groups was always very large, bilateral, and consistently observed in a similar anterior-posterior and medial-lateral position within the CC. Interestingly, a vestige of NeuN-positive cells was seen in a subset of control animals. When present in controls, it was unilateral, seen in very few sections, and was of much smaller area than in any PTU-treated animal. These findings confirm our previous observations and extend them to very modest reductions in TH in the dam. The presence of small heterotopia in some control animals suggests that this abnormality may represent an exaggeration of a normal developmental process. Identification using NeuN staining at the lowest dose of PTU indicates that this may represent a sensitive neurological marker of TH insufficiency. (Does not necessarily reflect EPA policy)

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