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The Pollutant Perfluorohexane Sulfonate (PFHxS) Reduces Serum Thyroxine but Does Not Alter Thyroid Hormone Action in the Postnatal Rat Brain

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Examination of PFHxS exposure and Developmental Neurotoxicity (DNT), and of the potential role of thyroid hormone Abstract: Per- and polyfluoroalkyl substances (PFAS) are surfactants utilized in an array of commercial products including nonstick cookware, stain resistant textiles, personal care products, and firefighting foam. Despite their widespread use, concerns regarding the safety of these compounds have been raised. One of the most reproducible effects of some PFAS is their ability to reduce serum thyroid hormones (THs) such as thyroxine (T4) and triiodothyronine (T3) in animal models. As THs are required for normal brain development, PFAS may also be developmental neurotoxicants. Here, we examine the endocrine and neurodevelopmental consequences of perfluorohexane sulfonate (PFHxS) exposure in pregnant, lactating, and developing rats, and compare its effects to the goitrogen propylthiouracil (PTU). We show that PFHxS dramatically reduces maternal serum T4, nearly equivalently to PTU (-55 and -51%, respectively). However, only PTU increases thyroid stimulating hormone (TSH). The lactational transfer of PFHxS is significant, and reduces pup serum T4 across the postnatal period. However, only PTU drastically reduces brain THs. Evaluation of brain TH action by phenotyping, RNA-Sequencing, and quantification of radial glia cell morphology supports that PTU interrupts brain TH signaling while PFHxS has limited to no effect. Overall, these data show that PFHxS induces abnormal serum TH profiles in dams and pups; however, there were no indications of hypothyroidism in the postnatal brain. We suggest the stark differences between the neurodevelopmental effects of PFHxS and a typical goitrogen may be due, in part, to the ability of PFHxS to interact with thyroid hormone distributing proteins like transthyretin

Impact/Purpose

Many per- and polyfluoroalkyl substances (PFAS) are thyroid disrupting chemicals, where exposure leads to abnormal serum thyroid hormone (TH) profiles in laboratory animals like rats. Environmental exposure to some PFAS are also associated with thyroid disorders in some human populations. As THs control normal brain development, understanding if and how PFAS can affect the thyroid system is critical for determining their risk. In this paper we examine how the contaminant perfluorohexane sulfonic acid (PFHxS) affects thyroid function in rat mothers and offspring. Rat pups born to PFHxS exposed mothers were evaluated for known indices of thyroid-mediated developmental neurotoxicity. In addition, we examined molecular readouts of TH action in the brain using RNA-Sequencing (RNA-Seq, transcriptomics) and cell morphology assays. Surprisingly, even though PFHxS demonstrated high lactational transfer and significantly reduced thyroid hormones like thyroxine (T4) in the dams and pups, the developing brain was unaffected. We next show evidence that PFHxS may interfere with some thyroid hormone distributing proteins in the rat, a mechanism supported by in vitro studies. In all, these data show that despite inducing abnormal serum thyroid hormone profiles, PFHxS is not a typical goitrogen and the developing brain maintains a euthyroid state. The chemical's mechanism of action can explain why the early postnatal brain was unharmed at the stages examined. These data are of interest to the IRIS program and OW, as PFHxS toxicity is currently being evaluated. 

Citation

O'Shaughnessy, Katherine, K. Bell, A. Sasser, M. Gilbert, C. Riutta, J. Ford, J. McCord, AND C. Wood. The Pollutant Perfluorohexane Sulfonate (PFHxS) Reduces Serum Thyroxine but Does Not Alter Thyroid Hormone Action in the Postnatal Rat Brain. Elsevier B.V., Amsterdam, NETHERLANDS, 190:108838, (2024). [DOI: 10.1016/j.envint.2024.108838]

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DOI: The Pollutant Perfluorohexane Sulfonate (PFHxS) Reduces Serum Thyroxine but Does Not Alter Thyroid Hormone Action in the Postnatal Rat Brain
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Last updated on November 13, 2024
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