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Ammonium Perchlorate Induces Thyroid Hormone Insufficiency and a Cortical Heterotopia in the Rat Brain
Gilbert, M., K. OShaughnessy, C. Wood, S. Thomas, J. Ford, AND I. Hassan. Ammonium Perchlorate Induces Thyroid Hormone Insufficiency and a Cortical Heterotopia in the Rat Brain. Society of Toxicology, San Antonio, Texas, March 11 - 15, 2018.
Abstract for poster/presentation at SOT National Meeting. Adverse Outcome Pathway development for developmental thyroid hormone disruption is in need of a clear downstream indicator of adversity in mammalian models. Cortical heterotopia is a brain malformation seen with exposure to pharmaceuticals that impair hormone synthesis. This abstract is preliminary data to suggest that is this action is generalizable to other hormone disruptors.
A morphological defect, a cortical heterotopia, has been observed in the brains of rat pups exposed in utero to moderate doses of the thyroid hormone (TH) synthesis inhibitor propylthioruracil (PTU). TH insufficiency during late gestation/early postnatal period is required to induce this defect, and its magnitude and incidence are dose-dependent. The present study extends these observations to the environmental contaminant ammonium perchlorate. Pregnant LE rat dams were placed on an iodine-controlled diet on gestational day (GD)2. On GD6, perchlorate (0 1 30 300 1000 ppm) was administered to the dam via the drinking water. In one group, blood and thyroid glands were collected from dams on GD20, and blood, brain, and thyroid glands were taken from the fetuses. In a second group, pups were sacrificed on PN0, PN2, PN14, and blood and brains were collected. Increases in thyroid gland weights were seen in dams on GD20 and PN14. Expression of gene transcripts (Nis, Tpo) was increased in the thyroid gland of the dam and the fetus on GD20 suggesting activation of the thyroid axis. Serum T4, but not T3, was reduced and TSH elevated in dams at 300 and 1000 ppm on GD20 and PN14. Serum T4 was also reduced in offspring on GD20 and PN0, but returned to control levels by PN2. This pattern suggests limited lactational transfer of perchlorate to the nursing pup. Brain T3 and T4 were reduced in the newborn (PN0). Expression of TH-response genes was not changed in the fetal brain. Histological analysis of the PN14 brain revealed heterotopia in 0%, 30%, 70% and 100% of animals at 0, 30, 300 and 1000 ppm dose, respectively. Heterotopia were also largest at the highest dose of perchlorate, but considerably smaller in size than those observed with PTU. These preliminary findings are consistent with prenatal TH insufficiency as essential for heterotopia formation, but further suggest that ‘perinatal’ hypothyroxenemia may be necessary for its full expression. Direct pup dosing studies are currently underway to address this hypothesis. These findings support the hypothesis that this morphological defect may serve as a brain-based biomarker of neurodevelopmental insult associated with moderate developmental TH disruption. Does not reflect EPA policy
Record Details:Record Type: DOCUMENT (PRESENTATION/POSTER)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
TOXICOLOGY ASSESSMENT DIVISION
ENDOCRINE TOXICOLOGY BRANCH