# Project 2 - Coupling Bioengineered and Computational Models of Thyroid Homeostasis to Support Human PCDD/F Risk-Assessment

> **NIH NIH P42** · MICHIGAN STATE UNIVERSITY · 2022 · $208,316

## Abstract

PROJECT SUMMARY/ABSTRACT
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, we model thyroid catabolism and action in human hepatocytes and determine effects
of PCDD/Fs exposure. To broaden assay coverage, we 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, we test targeted chemical mixtures.
In addition to hypothesis testing, this proposal 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.

## Key facts

- **NIH application ID:** 10353532
- **Project number:** 2P42ES004911-27A1
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Brian P. Johnson
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $208,316
- **Award type:** 2
- **Project period:** 1997-04-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10353532

## Citation

> US National Institutes of Health, RePORTER application 10353532, Project 2 - Coupling Bioengineered and Computational Models of Thyroid Homeostasis to Support Human PCDD/F Risk-Assessment (2P42ES004911-27A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10353532. Licensed CC0.

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