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Polybrominated Diphenyl Ether (DE-71)Interferes with Thyroid Hormone Action Independent Of Effects On Circulating Levels of Thyroid Hormone in Male Rats
Citation:
Bansal, R., D. Tighe, A. Denai, D. Rawn, D. Gaertner, D. Arnold, M. Gilbert, AND T. Zoeller. Polybrominated Diphenyl Ether (DE-71)Interferes with Thyroid Hormone Action Independent Of Effects On Circulating Levels of Thyroid Hormone in Male Rats. ENDOCRINOLOGY. Endocrine Society, 155(10):4104-12, (2014).
Impact/Purpose:
The EPA must evaluate the risk of exposure of the developing organism to chemicals with the potential to disrupt thyroid hormone (TH), and for which the degree of TH perturbation is likely to be fairly mild. The most frequently reported in vivo observation associated with thyroid disruptors is a reduction in circulating levels of TH. Polybrominated Diphenyl Ethers (PBDEs) are routinely found in human tissues including cord blood and breast milk and may interfere with TH during development. Animal studies have indicated that exposure to pregnant rats and mice leads to reductions in TH and neurobehavioral deficits in offspring. An untested underlying assumption is that PBDE effects on serum TH are indicative of PBDE effects on TH action in tissues. It is well known that TH action in tissues is controlled by several steps in addition to the regulation of TH levels in blood (i.e., active transport into tissues and cells, conversion of T4 to T3 by specific deiodinases enzymes, interaction with specific nuclear receptors). Thus, it is possible that some chemical exposures can alter the relationship between serum TN levels and downstream effects on TH action. The gold standard model for TH disruption is the TH synthesis inhibitor, propylthiouracil (PTU) which produces a very consistent and dose-dependent decrease in serum TH, concomitant increase in serum TSH, and downstream measures of TH action in tissues are tightly linked to serum T4 levels. The purpose of the present experiment was to test whether PBDE-induced changes in serum TH levels reflect PBDE-induced changes in TH action in liver and heart and contrast that to the PTU model system. Five concentrations of the PBDE mixture, DE-71 (0—30 mg/kg), were fed daily to pregnant rats from gestational day 6 to postnatal day 21. PBDEs were measured in dam liver and heart to estimate internal dose. Tissue PBDEs were in the ug/g lipid range, only slightly higher than observed in human fetal tissues. Results on indices of TH action were compared to four concentrations of propylthiouracil (PTU; 0, 1, 2, 3 ppm) provided to pregnant rats in drinking water for the same duration as for DE-71. PBDE reduced serum T4 similar to PTU, but did not increase TSH or produce expected effects on tissues. PTU treatment reduced T4 in liver and heart, but PBDE treatment reduced T4 only in heart. PBDE-treatment did not affect the expression of TH response genes in liver and heart as did PTU-treatment. A central conclusion is that serum T4 levels do not necessarily reflect downstream effects of chemical exposures on the thyroid system and may not always be a faithful proxy measure of chemical effects on the, ability of TH to regulate development and adult physiology. The implications of these fmdings are significant. First, a general assumption in environmental epidemiology is that relationships between chemical exposures and circulating TH are indicative or even predictive of relationships between chemical exposures and downstream events regulated by TH. Our current results indicate that this assumption may not always be true and should motivate the search for sensitive molecular biomarkers of TH action that may help to test that assumption in fhture studies. These results also indicate a lack of understanding of the dynamics of the hypothalamic-pituitary-thyroid axis and the ways in which it can be perturbed by chemicalldrug exposures. Finally, our results indicate that chemicals, especially mixtures, may affect the thyroid system at many different points of regulation that create effects that are not easily traced to TH disruption.
Description:
Polybrominated diphenyl ethers (PBDEs) are routinely found in human tissues including cord blood and breast milk. PBDEs may interfere with thyroid hormone (TH) during development, which could produce neurobehavioral deficits. An assumption in experimental and epidemiological studies is that PBDE effects on serum TH levels will reflect PBDE effects on TH action in tissues. To test whether this assumption is correct, we performed the following experiments. First, five concentrations of diphenyl ether (0-30 mg/kg) were fed daily to pregnant rats to postnatal day 21. PBDEs were measured in dam liver and heart to estmate internal dose. The results were compared with a separate study in which four concentrations of propylthiouracil(PTU; 0, 1, 2 , and 3 ppm) was provided to pregnant rats il drinking water for the same duration as for diphenyl ether. PBDE exposure reduced serum T4 similar in magnitude to PTU, but serum TSH was not elevated by PBOE, PBDE treatment did not affect the expression of TH response genes in the liver or heart as did PTU treatment. PTU treatment reduced T4 in liver and heart, but PBDE treatment reduced T4 on in the heart. Tissue PBDEs were in the micrograms per gram lipid range, only slightly higher than observed in human fetal tissues. Thus, PBDE exposure reduces serum T4 but does not produce effects on tissues typical of low TH produced by PTU, demonstrating that the effects of chemical exposure on serum T4 levels may not always be a faithful proxy measure of chemical effects on the ability of thyroid hormone to regulate development and adult physiology.