The long-term objective of this proposal is to characterize androgen and estrogen receptor activity and the androgen-metabolizing enzymes, 5-alpha-reductase and aromatase, in the fetal brain of rhesus monkeys (Macaca mulatta). The proposal will emphasize differences in fetal sex, stage of development (Days 35, 70, 100 and 165) and anatomical areas, particularly those brain regions which, in later development, may be involved in behavioral and neuroendocrine phenomena. We hope to identify specific sexual and tissue biochemical differences during the course of fetal development which could be correlated with potential organizational effects of steroid hormones. Specific objectives include: a) Evaluation of cytosol and nuclear androgen and estrogen receptor concentration; b) estimation of androgen and estrogen receptor association constants, chromatographic characteristics and binding affinities to potential steroid competitors (e.g., diethylstilbestrol and 17-OH-corticosteroids); c) measurement of 5-alpha-reductase (testosterone yield dihydrotestosterone) and aromatase (testoster one yield estradiol) velocities and Michaelis-Menten constants. Clinical and experimental evidence strongly support the hypothesis that in primates androgen rather than estrogen exposure during a critical period of fetal development controls sexual differentiation of the brain and behavior. As an indicator that circulating androgens are acting in the brain, one would expect to observe the appearance and subsequent increase in androgen receptor concentration during this critical period of sexual development (approximately Day 70 in monkeys). A sex difference between males and females in cytosolic/nuclear androgen receptor activity at this stage would further emphasize the importance of androgen exposure during this period of development. A delineation of sexual differences and temporal changes in receptor and enzyme levels will permit conclusions about whether circulating androgens and/or their metabolites are important for the organization of neural systems in primates. Our observations would provide evidence that there is a biochemical basis for behavioral and neuroendocrine disorders in patients exhibiting, e.g., testicular feminization and adrenogenital syndrome.
