Project 4

"Single Cell, Multi-Parametric High Throughput Platform to Classify Endocrine Disruptor Potential of Mixtures"

Michael Mancini and his team will concentrate on evaluating and reducing the human health risks posed by the exposure to hazardous substances, focusing on endocrine disrupting chemicals (EDCs), which are commonly found in natural and industrial sources and represent a large and growing family of compounds and mixtures; these EDCs are thought to impact reproduction and metabolism through action on the central nuclear receptors (estrogen, androgen, and thyroid receptors). The Galveston Bay/Houston Ship Channel area is highly industrialized and contains significant environmental pollutants, including EDCs; the region is susceptible to intense tropical storms, hurricanes, and floods, which are capable of mobilizing EDCs from sediments and other sources and depositing them inland, where they may pose a significant threat to the sizable population that lives there. Because there are currently no methods to quickly and cost-effectively assess the presence and health risks posed by EDCs after an environmental contamination event, the Mancini research team will work to develop a set of fast, sensitive, reproducible, and cost-effective high-throughput, single-cell imaging methods to determine the endocrine disrupting potential of complex chemical mixtures. By increasing the scope and relevance of EDC assessment, and by moving from analyzing single compounds to mixtures, the team hopes to develop ways to quickly identify the presence of EDCs, classify their bioactivity, and test the efficacy of remediation efforts from Project 2.

Relevance

Endocrine disrupting chemicals (EDCs) present a significant risk to human health through environmental human exposures and interactions with key endocrine nuclear receptors, effecting many central physiological processes, including reproduction and metabolism. EDCs are commonly found in natural and industrial sources and represent a large and growing family of compounds and mixtures that can be dispersed with sediments during weather-related disasters, which can pose significant exposure risk to the local communities. The high-throughput imaging platforms and custom automated web-based image analysis/reporting tools created by the Mancini team will facilitate health hazard evaluation and improve decision-making in response to natural and man-made environmental emergencies, thereby allowing officials to quickly assess the risks to human health during crisis situations.

The project will focus on three EPA-highlighted nuclear receptors: Estrogen (ER), Androgen (AR) and Thyroid (TR) hormone receptors. These primarily ligand-activated transcription factors are targeted both directly (binding) and indirectly (activity) by many common environmental toxicants derived from both natural and industrial sources, including pesticides, phytochemicals, heavy metals, plasticizers, etc.  The highly complex and multi-factorial mechanism of action of individual toxicants or mixtures upon nuclear receptor activities highlights the need for highly sensitive, multi-parametric, high-throughput assays.

Principal Investigators:

Co-Investigators:

  • Fabio Stossi, Baylor College of Medicine
  • Adam T. Szafran, Baylor College of Medicine



The overarching goal of this project is to develop fast, robust, and cost-effective high-throughput, single-cell imaging-based assays to determine the endocrine disrupting potential of complex, environmentally relevant chemical mixtures present in the highly industrial Galveston Bay/Houston Ship Channel area and other superfund sites.

 


Specific aims:

  1. Develop and improve upon existing, EPA-validated, high-throughput/ high-content imaging assays for ER, AR, and TR to generate large, single cell imaging-based datasets to evaluate compound bioactivity and endocrine disrupting potential.
  2. Via collaboration with the other projects and cores, use these datasets to validate a robust EDC classification model that will be challenged by analysis of laboratory designed and real-world environmental chemical mixtures.
  3. As the end goal of this project, predict how much endocrine disruptor bioactivity is present in environmental mixture from Superfund sites, how this activity changes during an environmental crisis, and which environmental toxicants are present in these real-life mixtures. Moreover, the knowledge generated also will inform on which remediation strategy is best depending on the mixture encountered during a crisis.