Developmental neurotoxicity of propylthiouracil (PTU) in rats: relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes.
Markedly lowered thyroid hormone levels during development may influence a child's behaviour, intellect, and auditory function. Recent studies, indicating that even small changes in the mother's thyroid hormone status early in pregnancy may cause adverse effects on her child, have lead to increased concern for thyroid hormone disrupting chemicals in the environment. The overall aim of the study was therefore to provide a detailed knowledge on the relationship between thyroid hormone levels during development and long-lasting effects on behaviour and hearing. Groups of 16-17 pregnant rats (HanTac:WH) were dosed with PTU (0, 0.8, 1.6 or 2.4 mg/kg/day) from gestation day (GD) 7 to postnatal day (PND) 17, and the physiological and behavioural development of rat offspring was assessed. Both dams and pups in the higher dose groups had markedly decreased thyroxine (T(4)) levels during the dosing period, and the weight and histology of the thyroid glands were severely affected. PTU exposure caused motor activity levels to decrease on PND 14, and to increase on PND 23 and in adulthood. In the adult offspring, learning and memory was impaired in the two highest dose groups when tested in the radial arm maze, and auditory function was impaired in the highest dose group. Generally, the results showed that PTU-induced hypothyroxinemia influenced the developing rat brain, and that all effects on behaviour and loss of hearing in the adult offspring were significantly correlated to reductions in T(4) during development. This supports the hypothesis that decreased T(4) may be a relevant predictor for long-lasting developmental neurotoxicity.
Department of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Søborg, Denmark. maap@food.dtu.dk
Marta
M
Axelstad
Pernille Reimar
PR
Hansen
Julie
J
Boberg
Mia
M
Bonnichsen
Christine
C
Nellemann
Søren Peter
SP
Lund
Karin Sørig
KS
Hougaard
Ulla
U
Hass
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D013956:Antithyroid Agents; D001309:Auditory Threshold; D001522:Behavior, Animal; D001835:Body Weight; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005865:Gestational Age; D006309:Hearing; D007037:Hypothyroidism / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018782:Maze Learning; D009043:Motor Activity; D009420:Nervous System / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D009929:Organ Size; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011441:Propylthiouracil; D051381:Rats; D017208:Rats, Wistar; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology; D013974:Thyroxine / Q000097:blood / Q000172:deficiency*
D013956:Antithyroid Agents; D011441:Propylthiouracil; D013974:Thyroxine