This application is being submitted to the ADAMHA Small Grant Program. The goal of this research is to establish an animal model of toluene embryopathy, a recently characterized clinical teratogenic syndrome described in offspring of women with a history of chronic toluene abuse. Clinically, this condition resembles fetal alcohol syndrome (FAS). Animal research has demonstrated that inhaled toluene is readily transferred to the fetus and to the developing central nervous system (CNS), however, specific toluene-induced gross malformations of the developing CNS have not been noted. Neither the microscopic neuropathologic effects nor the CNS biochemical consequences of prenatal toluene exposure have been studied. Aberrations of neuronal migration and other forms of cerebral dysgenesis have been observed in children with FAS. These CNS anatomic features, together with biochemical alterations, have been noted in animal models of FAS. Similar histologic and biochemical features, therefore, could underlie the clinical neurologic and behavioral impairment of toluene embryopathy. This hypothesis will be tested by studying neuronal generation and migration, the microscopic neuropathology, and the biochemistry of brain tissue from rats exposed to toluene in utero. Pregnant rats will be exposed to toluene by gavage administration on days 6 - 21 of gestation; maternal toxicity will be monitored, and fetotoxicity and general teratogenicity of toluene will be determined. Brain sections will be examined for pathologic changes for evidence of abnormal neuronal migration. Neuronal generation and migration will be evaluated further with 3H-thymidine autoradiography. Biochemical analysis to determine brain tissue ornithine decarboxylase activity and protein, DNA, and cholesterol content will be performed. Biochemical indices of brain growth and development will be calculated and the effects of prenatal toluene exposure on these parameters will be determined.
| Gospe Jr, S M; Zhou, S S (1998) Toluene abuse embryopathy: longitudinal neurodevelopmental effects of prenatal exposure to toluene in rats. Reprod Toxicol 12:119-26 |
| Gospe Jr, S M; Zhou, S S; Saeed, D B et al. (1996) Development of a rat model of toluene-abuse embryopathy. Pediatr Res 40:82-7 |
| Gospe Jr, S M; Saeed, D B; Zhou, S S et al. (1994) The effects of high-dose toluene on embryonic development in the rat. Pediatr Res 36:811-5 |
| Jones, A D; Dunlap, M R; Gospe Jr, S M (1994) Stable-isotope dilution GC-MS for determination of toluene in submilliliter volumes of whole blood. J Anal Toxicol 18:251-4 |
