Many changes occur in experimental animals (ob/ob mice) as a result of obesity. The ob/ob mice have been shown to be diabetic and have an increased level of insulin as well as corticosterone (Uysal et al., 1997). Others have also shown that there is an increased level of the cytokine, TNF-alpha, in the serum of these mice (Hotamisligil, 1993) which has been shown to cause a decrease in the level of testosterone in vitro (Xiong and Hales, 1993a). Regulation and expression of certain steroidogenic enzymes such as CYPO17c and CYPscc have been shown to be decreased following in vitro exposure of mouse Leydig cells to TNF-alpha. Changes in the steroidogenic enzymes may lead to decreased levels of testosterone which could ultimately affect the sterility of these animals. In this study, several protocols have been proposed that will be utilized to elucidate the mechanism by which TNF-alpha causes reduction of certain steroidogenic enzymes. The hypothesis of this study is that the increase in TNF-alpha, secondary to obesity, may cause a reduction in the levels or activity of some or all of the steroidogenic enzymes producing a decrease in testosterone production. A prolonged decrease in testosterone levels or production may affect spermatogenesis and thus contribute to male infertility or subfertility. Specifically, I propose the following: 1) To determine the changes in steroidogenic enzymes following the treatment of lean and ob/ob mice with TNF- alpha; 2) To determine the changes in steroidogenic enzymes following the treatment of lean and ob/ob mice with pentoxyfilline and antibodies directed to TNF-alpha; and 3) To determine the changes in steroidogenic enzymes in TNF-alpha receptor (both receptors) knockout ob/ob mice.
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