My proposed research will test the role of dietary soy phytoestrogens in the sexual differentiation of the mouse basal forebrain and subsequent activation of adult sexual and aggressive behaviors. Phytostrogens are biologically active non-steroidal molecules found primarily in soy products, legumes and whole grains. High concentrations of these compounds are increasingly being used as supplements in many consumer products marketed as natural alternatives to hormone replacement therapy and as preventative agents for hormone- and age-dependent cancers and diseases (2, 26). The roles of testosterone (T) and its aromatized metabolite, estradiol (E2), in sexual differentiation of the brain have been extensively examined, but only a handful of studies have examined a dimorphic role for phytoestrogens. Analysis of a standard soy-derived commercial laboratory diet revealed that isoflavone concentrations fed to rats and mice exceed endogenous estrogen levels by 30,000-60,000 fold (9). By comparison, serum isoflavone levels in infants fed soy formula are 13,000-22,000 fold higher than endogenous estradiol levels (38, 39). To explore their specific neuronal function, phytoestrogenic actions must be separated from those of endogenous E2. The aromatase knockout (ArKO) mouse provides a unique model to investigate phytoestrogen effects. These transgenic mutants lack the functional aromatase enzyme gene and are unable to produce endogenous estrogens, but they express both classic estrogen receptors (ERalpha, ERbeta), and thus can respond to exogenous estrogens. One bio-assay I have used to investigate phytoestrogenic actions is estradiol-mediated neural induction of progestin receptors (PR).
The specific aims of this proposal are first, to determine whether phytoestrogens affect organization and/or activation of PR induction. Secondly, I will manipulate developmental phytoestrogen exposure/intake and assess sexual behaviors in both male and female mice. Finally, I will determine whether aggression, a non-sexual behavior, and the neural peptide, arginine vasopression (AVP), are altered by phytoestrogen manipulation.
