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

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.全氟和多氟烷基物质（Per- and polyfluoroalkyl substances, PFAS）是一类被广泛应用于各类商业产品的表面活性剂，涵盖不粘炊具、防污纺织品、个人护理产品及消防泡沫等。尽管这类化合物应用广泛，但其安全性已引发诸多担忧。部分PFAS最具可重复性的效应之一，是能够在动物模型中降低血清甲状腺激素（thyroid hormones, THs）水平，如甲状腺素（T4）与三碘甲状腺原氨酸（T3）。由于甲状腺激素是大脑正常发育所必需的物质，PFAS也可能具备发育性神经毒性。本研究针对全氟己烷磺酸（perfluorohexane sulfonate, PFHxS）对妊娠、泌乳及发育中大鼠的内分泌与神经发育影响展开探究，并将其效应与致甲状腺肿物质丙基硫氧嘧啶（propylthiouracil, PTU）进行对比。结果显示，PFHxS可显著降低母体血清T4水平，降幅与PTU几乎相当（分别为-55%与-51%）。但仅PTU可升高促甲状腺激素（thyroid stimulating hormone, TSH）水平。PFHxS具有显著的泌乳转运效应，可在整个产后阶段降低仔鼠血清T4水平。然而，仅PTU可大幅降低脑组织甲状腺激素水平。通过表型分析、RNA测序（RNA-Sequencing）及放射状胶质细胞形态量化对脑组织甲状腺激素作用进行评估后发现，PTU会干扰脑组织甲状腺激素信号通路，而PFHxS仅存在极微弱甚至无此类效应。综上，本研究数据表明PFHxS可引发母鼠与仔鼠的血清甲状腺激素谱异常；但未观察到仔鼠产后脑组织存在甲状腺功能减退的迹象。我们推测，PFHxS与典型致甲状腺肿物质的神经发育效应存在显著差异，部分原因可能是PFHxS能够与转甲状腺素蛋白（transthyretin）这类甲状腺激素转运蛋白相结合。