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.
