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Thyroid Hormone Insufficiency in the Pregnant Rat Induces Cortical Heterotopia in Offspring: PTU vs Perchlorate
Gilbert, M., S. Spring, J. Ford, R. Ford, C. Wood, S. Thomas, K. OShaughnessy, M. Hotchkiss, Pat Kosian, AND S. Degitz. Thyroid Hormone Insufficiency in the Pregnant Rat Induces Cortical Heterotopia in Offspring: PTU vs Perchlorate. Developmental Neurotoxicology Society (DNTS), Denver, Colorado, June 24 - 29, 2017.
: This work will be used to understand mechanisms underlying brain malformations induced by thyroid hormone disruption. It represents a step to build an AOP for thyroid disruption and neurodevelopmental disorders..
We have previously reported the presence of a structural defect, a heterotopia in the brains of rat pups exposed in utero to 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 through the drinking water. Blood was sampled from the tail on GD15. At sacrifice on GD20, blood and thyroid glands were collected from dams; blood, brain, thyroid glands from fetuses. A subset of three dams from each of the 0, 30, 300 and 1000 ppm dose groups were maintained on perchlorate until postnatal day (PN)15. Pups were sacrificed on PN0, PN2, PN15 and blood and brains collected. Increases in thyroid gland weights and qPCR of transcripts (Nis, Tpo, Tg, TshR) in the thyroid gland of the dam and the fetus on GD20 revealed activation of the thyroid axis at the two highest dose levels. Serum T4 but not T3 was reduced in dams at 300 and 1000 ppm on GD15, GD20, PN15. Serum T4 was also reduced in offspring on GD20 and PN0, but unlike dams, had returned to control levels by PN2. Expression of TH-responsive genes in the fetal cortex (Bdnf, Bmp7, Dio2, Camkiv, Sema7a, Klf9, Slc7A3, ThrB) were not changed by perchlorate. A male and female pup from each litter sacrificed on PN15 revealed heterotopia (>0.025mm3) in 0%, 30%, 70% and 100% of animals at 0, 30, 300 and 1000 ppm dose, respectively. Although considerably smaller in size than that seen with PTU, heterotopia were larger at the highest doses of perchlorate. Although preliminary and based on a small sample size, these findings are consistent with prenatal TH insufficiency as essential for heterotopia formation. Further, they suggest that this structural anomaly may provide 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