Ethanol (Et0H) ingestion during puberty can cause profound, deleterious, and clinically significant hormonal changes in the developing mammal. These facts, coupled with the enormous problem of drinking in developing humans (i.e, teenage drinking) make it urgent that strategies be developed to prevent such hormonal consequences of Et0H, even in the face of continued Et0H ingestion. The major thrusts of this proposal are to determine the long term sequelae of Et0H exposure during this critical time period of fertility and bone development, the reversibility of these changes after withdrawal and the molecular and cellular mechanisms of specific preventive treatments. The hypotheses to be tested are: 1. The potent suppression of the peripubertal hypothalamic-pituitary-gonadal axis induced by acute or chronic Et0H can be prevented by either opiate receptor blockade or inhibition of endogenous nitric oxide synthase. 2. The suppression of the reproductive axis by Et0H in the peripubertal period results in long term deleterious consequences, including osteopenia and impaired fertility, which are only partially reversed after Et0H withdrawal. The animals are peripubertal male rats 42, 52, and 66 days old. The acute Et0H model is a single I.P. injection of Et0H (3 gm/kg) compared to saline with animals sacrificed at 1.5, 3, 6, and 24 hours after treatment. The chronic Et0H model is 14 days of feeding a liquid diet with 36% calories as Et0H compared to a control liquid diet and chow fed animals. Hypothalamic pituitary gonadal axis function will be measured by examining levels of hypothalamic LHRH mRNA, post synthetic processing of proLHRH to the mature, bioactive LHRH decapeptide, pituitary gonadotropin gene expression, and secretion, and serum testosterone levels, The ability of the opiate receptor blockers Naloxone and Nalterxone and of the nitric oxide synthase inhibitor L-NAME to prevent the deleterious consequences of acute or chronic Et0H exposure on the hypothalamic pituitary gonadal axis will be tested. In separate experiments animals will be fed Et0H or pair fed control diet or chow and assessed for fertility (by ability to impregnate females and testicular histology) and for development of osteoporosis. In a final experiment, animals will be alcohol or pair fed for 14 days, then put on ad lib chow diet for 90 days and examined for reversibility of impaired fertility or osteoporosis.
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