Thyroid hormone (TH) is essential for normal brain development in humans and in animals. Thus, it is important that a large number of manufactured chemicals can interfere with TH action, and by a variety of mechanisms. Some chemicals interfere directly with the TH receptor (TR) while others directly affect the thyroid gland, or serum binding proteins, deiodinases or transporters. The long- term goal of our work is to understand the mechanisms of ?thyroid disruption? and apply this to human populations. Our earlier work has demonstrated that specific polychlorinated biphenyls (PCBs) can activate the TR in a cell-based luciferase assay only if the enzyme CYP1A1 was induced and active. This enzyme can hydroxylate parent PCBs, and these OH-PCBs may then act directly on the TR or may act on other proteins that control TH action. Importantly, in animals treated with specific PCB congeners, there is a tight correlation between CYP1A1 induction and measures of TH action in the liver. More recently we have shown this to be true in human placenta as well: CYP1A1 expression was very strongly correlated with the expression of two genes directly regulated by TH ? Placental Lactogen (hPL) and Growth Hormone Variant (GHV). These findings are consistent with the proposition that manufactured chemicals may interfere with TH action during development in the absence of changes in serum TH concentrations. However, we have not identified the chemicals involved or the mechanism by which they may act. We propose now to pursue this work with two Specific Aims: First, to measure PCBs and OH-PCBs in the placental samples (n = 30) that had the highest and lowest CYP1A1 expression in our previous report. This comparison should identify specific congeners and metabolites that we can pursue in Specific Aim 2 to test their ability to the TR using cell-based and biochemical assays.

Public Health Relevance

Previous experimental work supports the hypothesis that some ubiquitous manufactured chemicals (e.g., polychlorinated biphenyls, PCBs, and polybrominated diphenyl ethers, PBDEs) can directly interfere with thyroid hormone (TH) action in tissue without affecting serum blood levels of TH. Our recent work in human placenta supports this hypothesis. Given the importance of TH in development, the goal of this work is to identify the specific PCB and PBDE metabolites that can interfere with TH action in human placenta, with strong implications for the fetus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES026228-01A1
Application #
9181216
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Schug, Thaddeus
Project Start
2016-09-30
Project End
2018-08-31
Budget Start
2016-09-30
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$239,250
Indirect Cost
$89,250
Name
University of Massachusetts Amherst
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003