Project Summary/Abstract Although synthetic chemicals have been used in consumer products for over a century, their use has rapidly outgrown our ability to regulate them for human health harm. Concerningly, the majority of these chemicals are not evaluated for potential toxicities towards human health. Even less is known about their developmental and reproductive toxicities, even for those routinely detected in maternal and umbilical cord sera during the vulnerable life-stage of pregnancy. There is a dire need for the novel generation of targeted developmental and reproductive toxicity data for environmental chemicals with known exposures during pregnancy, as well as robust methods to systematically interpret these data to support evidence-based policy- and decision-making. The long-term goal of this proposed project is to utilize established systematic review approaches to identify environmental chemicals of concern for human exposure with significant potential to cause developmental or reproductive toxicities and identify data gaps to focus high-throughput screening efforts. Our central hypothesis is that toxicological responses are driven by interactions between exogenous chemicals and biomolecular targets and that high throughput screening can be leveraged to predict harmful human health effects, specifically focusing on developmental and reproductive health endpoints. To test this, this proposed project will involve three Specific Aims: 1) Establish a digital knowledge base of comprehensive developmental/reproductive health endpoints and leverage results to validate existing in vitro mechanistic assays; 2) Assess and validate a prioritized chemical panel for reproductive toxicity using established HTS assays (yeast and C. elegans); and 3) Assess and validate a prioritized chemical panel for developmental toxicity using established in vitro human embryonic stem cell differentiation models. Collectively, these aims will achieve the goals of leveraging and integrating scientific findings from thousands of published studies on the topic of developmental and reproductive health in a comprehensive and systematic manner that will stimulate the rapid conduct of systematic reviews and chemical assessments on a scale not possible to date in the field of environmental health. It will also generate novel scientific data utilizing new approach methodologies targeted to fulfill existing research gaps and evaluate the relevance of animal- alternative test models for predicting adverse human health effects. Ultimately, this proposed project will provide critical insight that will accelerate and enhance the ability to assess relationships between environmental chemical exposures and human developmental and reproductive health outcomes.