In animal models phthalates and stress can alter fetal androgens and disrupt androgen-sensitive endpoints. We will examine associations between exposure to phthalates and psychosocial stress at multiple time points in early childhood development and androgen-sensitive reproductive, anthropometric, and neurodevelopmental endpoints. In The Infant Development and the Environment Study (TIDES) we confirmed that first trimester phthalate exposure is significantly and inversely associated with boy's anogenital distance (AGD) and that prenatal stress can modify this association. These novel findings suggest hypotheses that can be addressed with further follow-up of the TIDES cohort during middle childhood. We propose to extend our methodology in several novel directions in order to achieve our overarching goal of identifying the effects of exposure to phthalates and stress on androgen-sensitive development. Children born to TIDES mothers will be invited to two study visits between 3 and 6 years of age. At the 1st visit we will measure height, weight, skin fold thickness, and head circumference, and collect a sample of the child's urine for phthalate measurement. We will assess the child's attention, hyperactivity, social responsiveness, and play behavior by parental report. At the 2nd visit we will repeat these assessments and measure the length of the 2nd and 4th digits and their ratio as well as measuring the child's verbal ability and visuospatial reasoning by direct assessment. At each visit mothers will complete instruments designed to measure perceived stress, anxiety and depression, job stress and stressful life events. We will create a novel index that transforms the binary classification of se into a gender continuum score and examine its association with pre and postnatal exposure to phthalates and psychosocial stress. We hypothesize that physical measurements (AGD, digit ratio, head circumference) will be sensitive to prenatal exposure, while neurodevelopmental endpoints may be sensitive to both prenatal and postnatal exposure. We hypothesize that AGD will correlate with anthropometric outcomes as well as one or more neurodevelopmental endpoints such as play behavior as our preliminary data suggest. This study could have several implications for public health and environmental policy. Finding robust associations between developmental endpoints and phthalate exposure at current low levels would suggest the need for further reducing exposure. If newborn AGD predicts dimorphic development in multiple domains this would strengthen its importance as a marker of altered androgen-related development. If maternal stress modifies associations between phthalates and dimorphic development, as we have seen with AGD, this would lend support to efforts to reduce stress-related exposures during pregnancy. Any one of these findings from this large, robust, multi- center prospective study would support the hypothesis that a common androgen-dependent mechanism underlies these associations. Our findings could impact future research and policy because our study exposures are ubiquitous and many of our study endpoints, or their correlates, are early predictors of lifelong health. ExpandCollapse Abstract