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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007243-02
Application #
3110962
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1988-09-01
Project End
1991-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Albany Medical College
Department
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208
Brennan, R J; Mankes, R F; Lefevre, R et al. (1994) 4-Methylpyrazole blocks acetaminophen hepatotoxicity in the rat. Ann Emerg Med 23:487-94
Hubbell, C L; Mankes, R F; Reid, L D (1993) A small dose of morphine leads rats to drink more alcohol and achieve higher blood alcohol concentrations. Alcohol Clin Exp Res 17:1040-3
Mankes, R F; Battles, A H; LeFevre, R et al. (1992) Preferential alcoholic embryopathy: effects of liquid diets. Lab Anim Sci 42:561-6
van der Hoeven, T; Lefevre, R; Mankes, R (1992) Effects of intrauterine position on the hepatic microsomal polysubstrate monooxygenase and cytosolic glutathione S-transferase activity, plasma sex steroids and relative organ weights in adult male and female Long-Evans rats. J Pharmacol Exp Ther 263:32-9
Blanchard, B A; LeFevre, R; Mankes, R F et al. (1992) Hyperactivity and altered amphetamine sensitivity in premature juvenile rats. Brain Res Dev Brain Res 69:139-41
Mankes, R F; Glick, S D; Van der Hoeven, T et al. (1991) Alcohol preference and hepatic alcohol dehydrogenase activity in adult Long-Evans rats is affected by intrauterine sibling contiguity. Alcohol Clin Exp Res 15:80-5