Søderstrøm Sofie, Lille-Langøy Roger, Yadetie Fekadu, Rauch Mateusz, Milinski Ana, Dejaegere Annick, Stote Roland H, Goksøyr Anders, Karlsen Odd André
Department of Biological Sciences, University of Bergen, Thormøhlens gate 53 A/B, NO-5006 Bergen, Norway; Institute of Marine Research, Nordnesgaten 50, NO-5005 Bergen, Norway(1).
Department of Biological Sciences, University of Bergen, Thormøhlens gate 53 A/B, NO-5006 Bergen, Norway.
Environ Int. 2022 May;163:107203. doi: 10.1016/j.envint.2022.107203. Epub 2022 Mar 29.
Toxicity mediated by per- and polyfluoroalkyl substances (PFAS), and especially perfluoroalkyl acids (PFAAs), has been linked to activation of peroxisome proliferator-activated receptors (Ppar) in many vertebrates. Here, we present the primary structures, phylogeny, and tissue-specific distributions of the Atlantic cod (Gadus morhua) gmPpara1, gmPpara2, gmPparb, and gmPparg, and demonstrate that the carboxylic acids PFHxA, PFOA, PFNA, as well as the sulfonic acid PFHxS, activate gmPpara1 in vitro, which was also supported by in silico analyses. Intriguingly, a binary mixture of PFOA and the non-activating PFOS produced a higher activation of gmPpara1 compared to PFOA alone, suggesting that PFOS has a potentiating effect on receptor activation. Supporting the experimental data, docking and molecular dynamics simulations of single and double-ligand complexes led to the identification of a putative allosteric binding site, which upon binding of PFOS stabilizes an active conformation of gmPpara1. Notably, binary exposures of gmPpara1, gmPpara2, and gmPparb to model-agonists and PFAAs produced similar potentiating effects. This study provides novel mechanistic insights into how PFAAs may modulate the Ppar signaling pathway by either binding the canonical ligand-binding pocket or by interacting with an allosteric binding site. Thus, individual PFAAs, or mixtures, could potentially modulate the Ppar-signaling pathway in Atlantic cod by interfering with at least one gmPpar subtype.
全氟和多氟烷基物质（PFAS），尤其是全氟烷基酸（PFAA）介导的毒性，已与许多脊椎动物中过氧化物酶体增殖物激活受体（Ppar）的激活相关联。在此，我们展示了大西洋鳕鱼（Gadus morhua）的gmPpara1、gmPpara2、gmPparb和gmPparg的一级结构、系统发育和组织特异性分布，并证明羧酸PFHxA、PFOA、PFNA以及磺酸PFHxS在体外激活gmPpara1，这也得到了计算机模拟分析的支持。有趣的是，与单独的PFOA相比，PFOA和非激活型PFOS的二元混合物对gmPpara1产生了更高的激活作用，表明PFOS对受体激活具有增强作用。支持实验数据的是，单配体和双配体复合物的对接及分子动力学模拟导致鉴定出一个假定的变构结合位点，PFOS结合后该位点可稳定gmPpara1的活性构象。值得注意的是，gmPpara1、gmPpara2和gmPparb与模型激动剂和PFAA的二元暴露产生了类似的增强作用。这项研究为PFAA如何通过结合经典配体结合口袋或与变构结合位点相互作用来调节Ppar信号通路提供了新的机制见解。因此，单个PFAA或混合物可能通过干扰至少一种gmPpar亚型来潜在地调节大西洋鳕鱼中的Ppar信号通路。
