Organic solvents are recognized as possible factors or cofactors in the development of embryo toxic effects in humans and animals. Reports of the teratogenic effects of solvents have led to the suggestion of a fetal solvent syndrome (FSS) which is comprised of many of the same symptoms of the fetal alcohol syndrome (FAS) (Hersch, Podruch, Rogers & Weisskopf, 1985). The purpose of the present series of investigations is to identify and characterize, in mice, the behavioral and physiological consequences of in utero exposure to inhaled solvents subject to human abuse. The focus will be on tricholoroethane (TCE) and toluene due to their presence in numerous products inhaled by humans. Examinations of an animal model of fetal solvent syndrome will be conducted by exposing pregnant dams to solvents in sealed chronic inhalation chambers in order to examine the physiological and behavioral effects on the offspring. We propose to 1) investigate the teratogenic effects of an intermittent exposure regimen in an effort to develop an exposure regimen that is more characteristic of a solvent abuser, 2) examine the effects of paternal exposure to TCE and toluene on the CNS development of the offspring reared by dams unexposed to solvents, 3) attempt to reverse the detrimental effects to the offspring we found previously by administering a prostaglandin synthesis inhibitor to the dams while exposing them to the abused solvents and 4) conduct a series of systematic investigations varying the solvent concentration level (TCE-750, 4,000, 8,000 & 10,000 ppm; toluene-400, 800, 1200, 4000 ppm) in order to identify which levels are innocuous and result in fetal mortality and deformity. In the animal model, there is emerging evidence that some solvents produce pharmacological and behavioral effects similar to those of classical CNS depressant drugs (Evans & Balster, 1991) although the nature of the CNS effects produced by these exposures is not well established. Since an intact CNS is necessary for normal behavior and behavioral deficits may be most salient early in life (Spear, 1990) when the fully functioning CNS is necessary for the proper execution of behaviors, the goal of the present research is to examine the physical and neurobehavioral development of the offspring using landmarks of weight gain, eye and ear opening, incisor eruption (post-natal day 1-21) and testes descent/vaginal opening (PND 21-31) and behaviors that include: postural and rooting reflexes (PND 1-21) neuromuscular strength and coordination (PND 1-21), spontaneous activity (PND 23-25) and the capacity and plasticity of learning in adulthood (commence on PND 45). If results from my prior investigations demonstrating developmental delays and behavioral abnormalities in animals exposed in utero to TCE are successfully replicated, it would also be of interest to examine the animals' brain morphology. Neuropathic changes would be evaluated qualitatively for pathology and quantitatively for the area and volume of the total protein and glial fibrillary acid protein (GFAP) in the cerebellum, brainstem, hippocampus, and cortex.
| Ho, Meng-Chiao; Cassera, María B; Madrid, Dennis C et al. (2009) Structural and metabolic specificity of methylthiocoformycin for malarial adenosine deaminases. Biochemistry 48:9618-26 |
| Jones, H E; Balster, R L (1997) Neurobehavioral consequences of intermittent prenatal exposure to high concentrations of toluene. Neurotoxicol Teratol 19:305-13 |
