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Developmental Hypothyroidism Alters Brain-Derived Neurotrophic Factor (BDNF) Expression in Adulthood.
Citation:
LASLEY, B. L. AND M. E. GILBERT. Developmental Hypothyroidism Alters Brain-Derived Neurotrophic Factor (BDNF) Expression in Adulthood. Presented at Society of Toxicology 49th Annual meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
These data indicate that: 1) long lasting changes in BDNF expression emerge in adulthood following developmental hypothyroidism; 2) modest degrees of TH insufficiency are accompanied by cognitive impairments; and 3) a greater TH vulnerability may be present in males than in females
Description:
Severe developmental thyroid hormone (TH) insufficiency results in alterations in brain structure/function and lasting behavioral impairments. Environmental toxicants reduce circulating levels of TH, but the disruption is modest and the doseresponse relationships of TH and neurotoxicity not well defined. Neurotrophins are critical for development of neural connections and for synaptic plasticity. BDNF is highly expressed in developing brain and is reduced by severe hypothyroidism. Therefore we induced graded levels of developmental hypothyroidism by exposing pregnant rats to propylthiouracil (PTU 0, 1, 2 or 3 ppm) in the drinking water from gestational day 6 until postnatal day (PN) 22. This regimen produces 20-50% reductions in circulating levels of T4 in dams and pups without altering T3 or postnatal body weight. Animals received drug-free water postweaning, and TH levels return to normal by 2 weeks. One female from each litter was sacrificed on PN14 and PN21, and serum TH and BDNF protein expression determined. Cognitive function was assessed in offspring between PN60-PN90 using trace fear conditioning. At PN91-PN127 rats were sacrificed and blood/brain collected for TH and BDNF protein analysis. Context fear conditioning, a hippocampal-mediated function, was impaired in PTU-exposed males at all doses, but only at the highest dose in females. BDNF declined with age, but was 3-fold higher in hippocampus (Hc) and 33% higher in cortex (Ctx) in adult males than in adult females. BDNF was not altered by PTU at PN14 or PN21. Developmental hypothyroidism reduced BDNF in adult He and Ctx at 1 and 2 ppm, but not at the higher dose level. This pattern was more prominent in males. These data indicate that: 1) long lasting changes in BDNF expression emerge in adulthood following developmental hypothyroidism; 2) modest degrees of TH insufficiency are accompanied by cognitive impairments; and 3) a greater TH vulnerability may be present in males than in females. (Does not reflect US EPA policy)