In a recent study (Mankes and Glick, 1986), we found the developmental toxicity of ethanol was significantly influenced by intersibling contiguity. By extension from other published data, this increased toxicity of ethanol in the most masculine of the male pups was apparently due to an inhibition of fetal repair. In the most femininized offspring, prenatal ethanol exposure had less adverse effects since the higher levels of estradiol might enhance fetal repair (the concept of restitution and integrum of Neubert et al, 1980). The overall goal of this project is thus to directly evaluate the effect of sex steroids on the expression of experimental alcoholic embryopathy. Experiments will be done to refine and extend our initial observations by controlling for nutritional deprivation in a liquid diet, isocaloric replacement paradigm. Gas chromatographic measurements of blood alcohol levels and radio immunoassays of fetal and maternal sex steroid levels during critical developmental periods will facilitate inter-species extrapolations and increase our knowledge of the time course of sexual ontogeny. Other studies will be done to determine the uniformity of the ethanol induced damage in sexually undifferentiated rat fetuses, so as to establish a baseline for the estimation of sex steroid mediated intrauterine repair. Cross-fostering of pups of known contiguity types to normal rats will be done to establish whether prenatal ethanol exposure preferentially affects post-natal survival and growth. These studies will allow for further behavioral assessments of the interaction of prenatal alcohol with intrauterine sex steroids. Experiments will be done with alcohol consuming pregnant Sprague-Dawley strain rats and CD-1 mice to determine if intrauterine contiguity affects the expression of alcoholic embryopathy in other multiparous rodents. We will determine whether exogenous testosterone given to pregnant alcohol consuming rats increases alcohol's embryopathic effects. We will determine whether exogenous estradiol given to pregnant rats protects their offspring from alcohol's embryopathic effects. The proposed studies are significant in that they will increase our understanding of the role of sex steroids as modulators of normal and aberrant intrauterine growth and they offer the potential for the development of new chemotherapeutic strategies for the treatment of fetal alcohol syndrome in human infants.
