Superfund Research Program
Coupling Bioengineered and Computational Models of Thyroid Homeostasis to Support Human PCDD/F Risk-Assessment
Project Leader: Brian P. Johnson
Grant Number: P42ES004911
Funding Period: 2022-2027
- Project Summary
Project Summary (2022-2027)
Thyroid hormones (TH) act to regulate energy balance throughout the body by controlling energy expenditure inside each cell. Circulating levels of TH are controlled through hormone production and feedback in the hypothalamic-pituitary-thyroid (HPT) axis with the liver also playing a significant role. Diverse classes of chemicals cause TH imbalance through modulations of molecular targets involved in TH synthesis, transport, reception, metabolism, recycling, and feedback. Neurodevelopmental deficits, developmental hearing and vision dysfunction, metabolic disorders, and cancer, among other harms, are attributed to TH imbalance. Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) cause TH imbalance in human populations and animal models although the mechanism is unresolved. The long-standing mechanistic paradigm whereby PCDD/Fs activate the aryl hydrocarbon receptor (AHR) in hepatocytes inducing TH-glucuronide formation and clearance has recently been put into question based on data generated in glucuronidation deficient rodent models.
This project aims to elucidate the mechanism by which PCDD/F exposures disrupt human thyroid kinetics and action through the co-development of computational models and a microphysiological thyrocyte/hepatocyte screening model that together can support risk-assessment by bridging experimental data in human based culture systems with a population-level understanding of potential effects on human health. To elucidate the mechanism of PCDD/F induced thyroid imbalance, the team models thyroid catabolism and action in human hepatocytes and determine effects of PCDD/Fs exposure. To broaden assay coverage, the researchers develop and test a thyrocyte/hepatocyte model that incorporates TH synthesis. To determine the potential for synergistic effects between PCDD/Fs and commonly co-exposed chemicals acting through alternate molecular initiating events, targeted chemical mixtures are tested.
In addition to hypothesis testing, this project refines computational and microphysiological models to evaluate the effects of chemicals on human thyroid signaling that could be used by stakeholders in the regulatory, research and regulated community. The improved predictive potential of microphysiological in vitro chemical testing linked through computational modeling to population health outcomes is a critical step toward supporting PCDD/F risk-assessment. Improved risk-assessment can then guide targeted intervention strategies that prevent adverse health effects in sensitive populations.