The specific aims of this grant proposal are to determine the consequences of paternal alcohol exposure on the outcome and development of their progeny. In several recent studies, we observed a number of behavioral and endocrinological abnormalities in the offspring of male rats who's fathers consumed alcohol during adolescence. In addition, we have observed a marked degree of tolerance to alcohol's effects and an enhanced sensitivity to other psychoactive drugs. These abnormalities in the offspring wee evident even though the amount of alcohol consumed by the fathers was only moderately intoxicating and despite the fact that breeding occurred following an extended alcohol-free period. The studies in this grant proposal will continue our analysis of the paternal effects of alcohol and address issues important for understanding the parameters involved and underlying mechanisms.
Our specific aims are: First, to further characterize the deficits observed in male and female offspring of alcohol-exposed rats, including endocrinological and learning deficits. Second to examine in detail whether the acute sensitivity to alcohol and other psychoactive drugs, the development of tolerance and physical dependence on alcohol and other abused substances and the self selection of alcohol are altered in the offspring of alcohol-exposed fathers when compared to controls. Third, to determine whether the age of initial paternal exposure to alcohol is a critical factor in the deficits observed in their offspring (eg, does early exposure to alcohol produce greater deficits in subsequent offspring than does alcohol exposure in adults?). Fourth, to determine how much alcohol and over what duration is necessary to produce paternal alcohol effects on their offspring. Fifth, to determine whether the deficits observed in the offspring of alcohol-exposed male rats persist in subsequent generations resulting from breeding male and female alcohol- derived offspring. The proposed studies could have far-reaching clinical significance since alcohol abuse is increasing in adolescent boys and we know very little about the consequences of such abuse on their subsequent reproductive behavior, fertility and the outcome of their offspring. Moreover, in view of the findings that appears to be genetically linked to the fathers and that their sons appear to have significant physiological and behavioral deficits, it seems clear that the possibility of effects of paternal alcohol administration on fertility and fetal outcome should be explored. Based upon our preliminary data, our animal model may have unique clinical significance since the effects we have observed in the rat are similar to those found in the offspring of human alcoholic fathers: gender-specific cognitive and endocrine disturbances and differences in the sensitivity to alcohol challenges without evidence of gross malformation or severe developmental anomalies. The proposed studies could thus be instrumental in focussing on an important variable leading to birth defects and possibly the transmission of alcoholism.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Biochemistry, Physiology and Medicine Subcommittee (ALCB)
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Washington University
Schools of Medicine
Saint Louis
United States
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Cicero, T J; Nock, B; O'Connor, L et al. (1994) Acute alcohol exposure markedly influences male fertility and fetal outcome in the male rat. Life Sci 55:901-10
Cicero, T J; Nock, B; O'Connor, L H et al. (1994) Acute paternal alcohol exposure impairs fertility and fetal outcome. Life Sci 55:PL33-6
Adams, M L; Meyer, E R; Sewing, B N et al. (1994) Effects of nitric oxide-related agents on alcohol narcosis. Alcohol Clin Exp Res 18:969-75
Adams, M L; Meyer, E R; Sewing, B N et al. (1994) Effects of nitric oxide-related agents on rat testicular function. J Pharmacol Exp Ther 269:230-7
Adams, M L; Forman, J B; Kalicki, J M et al. (1993) Antagonism of alcohol-induced suppression of rat testosterone secretion by an inhibitor of nitric oxide synthase. Alcohol Clin Exp Res 17:660-4
Adams, M L; Kalicki, J M; Meyer, E R et al. (1993) Inhibition of the morphine withdrawal syndrome by a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester. Life Sci 52:PL245-9
Cicero, T J; Nock, B; O'Connor, L (1993) Naloxone does not reverse the inhibitory effect of morphine on luteinizing hormone secretion in prepubescent male rats. J Pharmacol Exp Ther 264:47-53
Adams, M L; Sewing, B; Forman, J B et al. (1993) Opioid-induced suppression of rat testicular function. J Pharmacol Exp Ther 266:323-8
Little, P J; Adams, M L; Cicero, T J (1992) Effects of alcohol on the hypothalamic-pituitary-gonadal axis in the developing male rat. J Pharmacol Exp Ther 263:1056-61
Adams, M L; Nock, B; Truong, R et al. (1992) Nitric oxide control of steroidogenesis: endocrine effects of NG-nitro-L-arginine and comparisons to alcohol. Life Sci 50:PL35-40

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