Toluene is a widely used solvent which finds applications as a starting material in the manufacture of a variety of organic compounds, as well as a solvent in numerous industrial products. In addition to occupational and environmental exposures, an increasingly popular way of exposure to toluene has been its abuse by sniffing. Animal and human studies have indicted that a major target for toluene toxicity is the central nervous system. Over the past two decades, evidence has also accumulated, primarily through case reports in humans, that toluene may also be a developmental neurotoxicant. Children born from toluene-abusing women display a syndrome characterized by growth retardation, microencephaly and particular facial characteristics. The effects are strikingly similar to those observed in the Fetal Alcohol Syndrome, however, no animal models or mechanistic information exist on toluene embryopathy. Based on our own and others' experience in studying the developmental toxicity of ethanol, we propose to carry out a series of in vivo and in vitro experiments to provide initial information on the developmental effects of toluene. The proposal will focus on microencephaly, which has been seen in most cases of toluene embryopathy, and seems to persist at least into early childhood. The two specific aims of this proposal are: 1. To develop an animal model, in the rat, for toluene-induced microencephaly. For this purpose, pups will be treated with toluene postnatally during the brain growth spurt, at different dosages and times, and brain weights and toluene levels will be measured. 2. To test the hypothesis that toluene-induced microencephaly may be due, at least in part, to its ability to inhibit proliferation of glial cells induced by various mitogens. This will be accomplished by studying proliferation of rat cortical astrocytes and human astrocytoma cells in vitro. These experiments will provide sufficient pilot data to pursue both in vivo and in vitro studies, aimed at defining the characteristics and mechanisms of toluene developmental neurotoxicity.
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