Neurological consequences of congenital hypothyroidism in Fischer 344 rats.
Congenital hypothyroidism was induced in rat pups by treating pregnant and lactating dams with an antithyroid drug, methimazole. Methimazole (0.00, 0.01, 0.03 or 0.10 mg/ml) was added to the drinking water of female Fischer 344 rats from gestational day 17 through lactational day 10. The same animals as pups and adults were evaluated with a developmental neurotoxicological test battery. Pups were evaluated for physical measures of maturation, thermoregulation, flash evoked potential (FEP), motor activity, and morphology of brain, thyroid and kidneys. Parameters evaluated in the same animals as adults were body weight, functional observational battery, grip strength, body temperature, and neurological tests (FEP, auditory brainstem response to 4 and 16 kHz tone pips (ABR4, ABR16) and clicks (ABRc), somatosensory evokes potentials recorded from the somatosensory cortex (SEP-S) and the cerebellum (SEP-C), and caudal nerve action potential to single and paired stimuli (CNAP). Treatment-related findings in pups included slightly decreased body weight, slightly increased kidney weights, altered thyroid morphology, delayed incisor eruption, decreased thermoregulation, and FEP changes. Although a pup no effect level was not determined, effects at 0.01 mg/ml were minimal. Adult ABR4 and ABR16 waveforms were slower than controls and had altered shapes; ABRc, SEP-S, and SEP-C waveforms exhibited reduced power, increased latency and altered shape. Effects were detected in adults at all doses and thus, the neurological characteristics of rat congenital hypothyroidism were clearly detected with this developmental neurotoxicological test battery. The effects on body weight, kidney weight and thyroid morphology, however, suggest a general developmental effect and nervous system function did not appear to be preferentially affected.
Albee
R R
RR
Mammalian and Environmental Toxicology Research Laboratory, Dow Chemical Co., Midland, MI 48674.
Mattsson
J L
JL
Johnson
K A
KA
Kirk
H D
HD
Breslin
W J
WJ
D000818:Animals; D000831:Animals, Newborn; D001833:Body Temperature Regulation / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D001933:Brain Stem / Q000503:physiopathology; D003409:Congenital Hypothyroidism; D005071:Evoked Potentials / Q000187:drug effects; D005260:Female; D005425:Flicker Fusion / Q000187:drug effects; D007037:Hypothyroidism / Q000139:chemically induced / Q000503:physiopathology; D007774:Lactation; D008098:Litter Size / Q000187:drug effects; D008297:Male; D008713:Methimazole / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D009132:Muscles / Q000187:drug effects / Q000503:physiopathology; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains
D008713:Methimazole