Alcoholism in women leads to significant aberrations in reproductive system function such as, amenorrhea, dysmenorrhea, anovulation, infertility, luteal phase defects, earlier menopause and increased rates of spontaneous abortions. Only some of these changes appear to be reversible. Recent data suggest that reproductive system dysfunction is also observed in non alcoholic women who are alcohol abusers. Even though data suggest the ethanol may exert detrimental effects on the hypothalmopituitary axis and or the ovary, the site(s) and mechanisms(s) of alcohol toxicity on the reproductive tract are poorly understood. The long term objectives of the proposed research are to understand the mechanisms of alcohol toxicity on the ovary. Previous research indicated that chronic alcoholism may produce significant ovarian dysfunction and morphological changes with consequent decreases in steroid hormone secretion, and these effects may give rise to much of the reproductive toxicity of ethanol. To understand the toxicity of alcohol on reproductive function at the molecular level it is imperative to develop suitable in vitro models. Recently a tissue culture system where human granulosa lutein (LG) cells are exposed to constant """"""""physiological"""""""" concentrations of ethanol has been developed. In this system ethanol selectively inhibited stimulatory effects of LH on steroidogenesis. This system will be used to study the mechanism of toxicity of ethanol directly on human LG cells and human ovarian cells. Planned experiments are the following; studies of ethanol action on LH receptor number and affinity using iodo hormone binding and independent evaluation of LH receptor number with LH receptor antibodies, alcohol action on LH receptor, guanine binding protein (G protein) interactions and effects of ethanol on G protein coupling to adenylate cyclase. Since LH may act on steroidogenesis via the Ca++/inositol phosphate/diacylglycerol/protein kinase C pathway, actions of ethanol on components of this system will be measured to determine whether ethanol can modulate LH's physiologic effects via this pathway. A cultured rat LG cell model will be developed to try and duplicate the effects of alcohol on human LG cells and from these studies we hope to establish the mechanisms by which alcohol acts as a direct gonadal toxin.
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