The Harvard-Mexico Project on Fetal Lead Exposure, Risks and Intervention Strategies (FLERIS), a collaboration between investigators at Harvard University and the National Institute of Public Health in Mexico, has been a model of international teamwork and environmental epidemiology using state-of-the-art methods that won the 1999 NIEHS Progress and Achievement Award. FLERIS established three birth cohorts using similar methods that we continue to follow. In this revised competitive renewal of our R01, we propose to follow-up, collect and analyze new data and samples on all three cohorts and fully capitalize on its rich associated bank of archived data and samples to address two major themes representing novel hypotheses with critical implications for public health: (A) the potential of fetal neurotoxicant exposure to negatively impact on child behavior (aggression and attention deficit/hyperactivity); and (B) the potential for the impact of fetal neurotoxicant exposures on both cognition and behavior to be modified by gene-environment interactions involving candidate genes critical to CNS cholesterol metabolism. Our primary fetal exposure of concern will remain environmental lead exposure, because of its continuing primacy as an environmental hazard in the United States and Mexico. We have chosen specific genes because of growing evidence for the centrality of cholesterol metabolism to neurodevelopment, intriguing preliminary data pointing to cholesterol gene-lead interactions recently published by our group, and new unpublished but supportive data produced for this re-submission. We will also examine several exploratory hypotheses that attempt to develop pre-pulse inhibition as an early predictor of lead's impact on behavior and that assess the potential for measures of maternal circulating cholesterol, maternal dietary cholesterol, and infant 24S-hydroxy cholesterol (a novel plasma biomarker of CNS cholesterol) to modify the lead-gene interactions with respect to cognition and behavior. Finally, we will use our data to compare the relative impacts of prenatal with postnatal lead exposure. This research promises to provide key insights into mechanisms of neurotoxicity, individual susceptibility, and both behavior and cognition as toxic endpoints. ExpandCollapse Abstract