This R21 proposal is based on the hypothesis that prenatal exposure to phthalate esters will alter normal brain development and associated behavioral outcomes. Phthalates are ubiquitous environmental contaminants found in cosmetics, household furnishings, medical devices, toys, and numerous other products. Human exposures are universal. Recent human data, showing a significant relationship between levels of phthalate metabolites in maternal urine during pregnancy and shortened anogenital distance in male children, provoke concerns that phthalates may pose significant threats to neurobehavioral development. In rats, exposure during gestation to certain phthalates induces malformations in the reproductive tract of male offspring as well as markers of feminization such as shortened anogenital distance. This syndrome signifies a disturbance in androgen-mediated development attributable to a decrease in fetal testicular production of testosterone. Because testosterone governs sexual differentiation of the brain, reductions in fetal output would be expected to engender demasculinization of brain anatomy and its expression in behavior. To test this hypothesis, pregnant rats will be administered selected phthalate esters (diethylhexyl phthalate, or DEHP, and dibutyl phthalate, or DBP), or a combination of the two, during gestational days 12-20, which encompass the testosterone surge in fetal males. Both male and female offspring will be evaluated behaviorally and morphologically, with an emphasis on behaviors and structures recognized as sexually dimorphic. Behavioral measures include play behavior, exploratory behavior, saccharin preference, sex partner preference, and schedule-controlled operant behavior. Morphological assessments are based on the volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA). This research addresses an urgent question arising from the human data. It will enable us to use the rat as a laboratory model for human phthalate exposures during fetal development, to carefully control exposure dose and timing, and to to amplify and extend the epidemiological findings by subjecting certain of their implications to laboratory investigation. Phthalate esters are chemicals used as plasticizers in personal care items such as shampoos, medical tubing, plastic toys, food packaging, and many other products. They impair male reproductive system development in animal models, and recent studies show similar effects in humans. Because phthalates act as anti-androgens, they have the potential to interfere with human brain and behavioral development. The proposed research will examine this question in rats, and translate its implications into human relevance. ? ? ?
