Absence of developmental effects in CF-1 mice exposed to aspartame in utero.

Aspartame (L-aspartyl-L-phenylalanine methyl ester) is a widely used high potency dipeptide sweetener. Developmental toxicology studies have been performed in several species documenting no effects of high doses of aspartame. Recently, a study by Mahalik and Gautieri [1984) Res. Commun. Psychol. Psychiatry Behav. 9, 385-403) reported a delay in the achievement age for the visual placing response in mice pups after maternal administration of high dosages of aspartame during late gestation. In the present study developmental parameters were determined in offspring of CF-1 mice after maternal administration of aspartame at 500, 1000, 2000, and 4000 mg/kg body wt by oral gavage. Aspartame was administered on Days 15 through 18 of gestation. Maternal body weight, food consumption, gestation length, reproductive indices, and litter size were not affected by aspartame treatment. In the pups, body weights, negative geotaxis, and surface and midair righting reflexes were not altered by treatment. There was no delay in the development of the visual placing response regardless of the method employed for assessment (grid or rope) or the manner by which the data were analyzed. There were also no changes in time of eye opening, reflex pupil closure, and ophthalmoscopic examination in the offspring. Thus, neither physical nor functional development was altered in mice after in utero exposure to extremely large dosages of aspartame. More specifically, in utero exposure to aspartame did not affect the development of the visual system in mice.

Changes in thyroidal function and liver UDPglucuronosyltransferase activity in rats following administration of a novel imidazole (SC-37211).

SC-37211, an imidazole with antianaerobic activity, was administered po to male rats for 2 weeks at dosages of 20, 60, and 200 mg/kg/day. Histological changes in the thyroid included irregularly shaped follicles and slightly enlarged follicular cells. Serum triiodothyronine (T3) and/or thyroxine (T4) were significantly decreased in treated animals at all dosages; these decreases were not observed following a 2-week recovery period. The half-life of serum [125I]thyroxine was also significantly decreased in rats treated with SC-37211. Morphological changes in the thyroid are likely the result of thyroid-stimulating hormone (TSH) stimulation, a response to decreased serum T3 and T4 concentrations. The decreases in T3 and T4 were not due to decreases in iodide uptake or organification. There were dose-dependent increases in liver weights, liver-to-body weight ratios, and UDPglucuronosyltransferase activity toward p-nitrophenol and T4. Therefore, the decreases in serum T3 and T4 were probably due to an increase in hepatic metabolism rather than to a direct effect of SC-37211 on the thyroid.

Behavioral consequences of perinatal hypothyroidism in postnatal and adult rats.

The long-term effects of perinatal hypothyroidism on spontaneous locomotor behaviors were assessed after exposure to the antithyroid drug, methimazole. Perseveration was observed in methimazole-treated rats in a spatial maze. Locomotor activity in residential mazes was examined at 6 weeks, 4 months, and 6 months of age. Treated rats were hypoactive at some intervals compared with controls and were hyperactive at others. These paradoxical differences resulted from changes in exploratory, diurnal, and nocturnal locomotor activity in control rats both with increasing age and on repeated exposures to residential mazes; rats after perinatal hypothyroidism had relatively constant levels of activity on repeated days of exposure to residential mazes and at different ages. These results may be related to perseveration noted in the spatial maze. In an analysis of walking patterns, treated rats tended to have a more pronounced asymmetry in gait than controls.

Early development in the caudate and thyroid of methimazole-treated rats.

Rat pups were made hypothyroid by administration of the antithyroid agent, methimazole, to pregnant and lactating dams from gestational day 17 to postnatal day 10. Dendritic branching of caudate neurons in methimazole-treated pups was decreased 30 to 40 percent between 1 and 28 days of age. Perinatal methimazole treatment produced a pattern of developmental deficit or prolonged delay in the growth of dendrites of caudate interneurons. The antithyroid effect was also apparent in morphometric changes in the thyroid gland of methimazole-treated rats. Functional tissue was present at all ages examined. Colloid storage in the thyroid was decreased during methimazole administration compared with colloid storage after methimazole was discontinued. Both during and after methimazole administration the size of thyroid follicular cell nuclei in methimazole-treated pups was significantly greater than that of thyroid nuclei in control animals. Changes in dendritic branching, body weight and thyroxine levels lasted into adult life but recovery toward control levels was seen in adults. These changes in offspring following maternal administration of a goitrogen were demonstrated at an exposure level well below complete thyroid suppression.