Relative cerebellar weight: A potential indicator of developmental neurotoxicity

Abstract

Overt malformations do not always accompany behavioral changes resulting from perinatal exposure to certain drugs. However, the central nervous system (CNS) is the anatomical substrate for behavior, and functional defects may be accompanied by more subtle, structural alterations of the brain. The purpose of this study was to determine if changes in the weights of certain brain regions occur in rats exposed prenatally and/or perinatally to propylthiouracil (PTU) which retards functional development of the brain. Pregnant rats were dosed with PTU during gestation and/or lactation, and on postnatal day 28, auditory startle responses were measured to determine if PTU altered functional development. The brains of all pups were then dissected into 10 separate regions, dried and individually weighed. Brain weights were expressed in absolute and relative (to total brain weight) terms. Pups that were exposed to PTU from days 10 to 21 of gestation grew normally, but their startle responses to auditory stimuli were significantly different ( p<0.05) from controls. Thus, for the purpose of this experiment, PTU acted as a developmental neurotoxicant because it altered performance on a test of neuromuscular function without being overtly teratogenic. The weights of most brain regions in PTU-treated rats were statistically comparable to controls. However, relative cerebellar weight was significantly ( p<0.05) different. Therefore, these data suggested that relative cerebellar weight might be used to predict functional defects that appear during development following prenatal or perinatal exposure to certain neurotoxicants. Although cerebellar weight and auditory startle responses were altered by PTU, this study does not establish a causal relationship between the anatomical and functional changes that occurred. However, the anatomical correlation of altered startle responses suggests that relative cerebellar weight may be a useful measure of developmental neurotoxicity. Since neurogenesis in the rat cerebellum begins early in gestation and continues for several weeks after birth, it is vulnerable to perturbation by drugs for an extended time during development Thus cerebellar weight, which is easily monitored, may be an anatomical predictor of functional development that can be used to complement findings from more conventional performance tests for developmental neurotoxicity.