Implementation of a primary screen for developmental neurotoxicity.
A battery of tests to evaluate physical growth/development and neurobehavioral function was conducted with 78 litters of control Sprague-Dawley rats given purified water by intubation. The objectives of this study were to optimize test methods and to document the range and variability of the experimental endpoints. Data are presented for maternal evaluations (body weight gain, food consumption), gestation length, litter size, and postnatal survival. Pup body weight was used to assess postnatal somatic growth rate from birth to 85 days of age, while whole and regional brain weight measurements at 7, 28, and 85 days provided a more specific measure of physical growth relevant to a neurobehavioral study. Physical landmarks of development evaluated were pinna unfolding, incisor eruption, and eye opening while reflex landmarks of development evaluated were the negative geotaxis and pupillary reflexes. The mean percentage of litters acquiring a physical trait or reflex increased sigmoidally with age, and the data suggest that the potential to detect developmental delays would be optimal when ca. 90% of control litters reach the test landmark. Functional evaluations were arranged according to four testing subsets so that each litter was evaluated in each test (1 pup/sex/litter), but repeated testing on pups was minimized. Auditory and tactile startle reflexes, as well as prepulse inhibition, were measured at ages 22 days and 60-64 days and found to increase with age. A passive avoidance paradigm (age 40-43 days) was used to assess exploratory behavior (approach) and memory (avoidance). Swimming performance in a water maze was used to evaluate learning. In this test, escape times and error rates improved to their highest level by five or six trials and showed acceptable degrees of variability. Spontaneous motor activity was monitored for 23 hr at age 54-61 days to evaluate exploratory activity, photoperiod entrainment, and catecholamine-induced locomotion (amphetamine challenge). Finally, landmarks of sexual maturation (balanopreputial separation evident at 45 days of age, vaginal perforation evident at 33 days) and estrous cyclicity (4.8 cycles per 21 days) were evaluated as measures of reproductive neuroendocrine function. In sum, the test battery provided an efficient yet comprehensive screen for evaluating effects on physical growth/development and neurobehavioral function which meets practical criteria for preclinical testing of pharmaceutical agents.
Department of Reproductive and Developmental Toxicology, Smith Kline and French Laboratories, King of Prussia, Pennsylvania.
P J
PJ
Wier
F J
FJ
Guerriero
R F
RF
Walker
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D007858:Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D012018:Reflex / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects; D012098:Reproduction / Q000187:drug effects