PDF(Pubmed)
Abstract：
Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and organ injuries. Per- and polyfluoro alkyl substances (PFAS) and polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that bioaccumulate and have been associated with steatosis in the liver. Although PFAS and PAH are classified as chemicals of concern, their molecular mechanisms of toxicity remain to be explored in detail. In this study, we aimed to identify potential mechanisms by which an acute exposure to PFAS and PAH chemicals can induce lipid accumulation and whether the responses depend on chemical class, dose, and sex. To this end, we analyzed mechanisms beginning with the binding of the chemical to a molecular initiating event (MIE) and the consequent transcriptomic alterations. We collated potential MIEs using predictions from our previously developed ToxProfiler tool and from published steatosis adverse outcome pathways. Most of the MIEs are transcription factors, and we collected their target genes by mining the TRRUST database. To analyze the effects of PFAS and PAH on the steatosis mechanisms, we performed a computational MIE-target gene analysis on high-throughput transcriptomic measurements of liver tissue from male and female rats exposed to either a PFAS or PAH. The results showed peroxisome proliferator-activated receptor (PPAR)-α targets to be the most dysregulated, with most of the genes being upregulated. Furthermore, PFAS exposure disrupted several lipid metabolism genes, including upregulation of fatty acid oxidation genes (Acadm, Acox1, Cpt2, Cyp4a1-3) and downregulation of lipid transport genes (Apoa1, Apoa5, Pltp). We also identified multiple genes with sex-specific behavior. Notably, the rate-limiting genes of gluconeogenesis (Pck1) and bile acid synthesis (Cyp7a1) were specifically downregulated in male rats compared to female rats, while the rate-limiting gene of lipid synthesis (Scd) showed a PFAS-specific upregulation. The results suggest that the PPAR signaling pathway plays a major role in PFAS-induced lipid accumulation in rats. Together, these results show that PFAS exposure induces a sex-specific multi-factorial mechanism involving rate-limiting genes of gluconeogenesis and bile acid synthesis that could lead to activation of an adverse outcome pathway for steatosis.
摘要：
具有在人类和动物体内生物蓄积潜力的有毒物质长期以来一直是人们关注的问题，特别是由于它们与多种疾病和器官损伤有关。全氟烷基和多氟烷基物质（PFAS）和多环芳烃（PAH）是两种此类化学物质，它们会在肝脏中产生生物累积并与脂肪变性有关。虽然PFAS和PAH被归类为关注的化学品，其毒性的分子机制仍有待详细探讨。在这项研究中,我们的目的是确定急性暴露于PFAS和PAH化学物质可以诱导脂质积累的潜在机制，以及反应是否取决于化学类别，剂量,和性爱。为此,我们分析了从化学物质与分子起始事件(MIE)结合以及随之而来的转录组改变开始的机制.我们使用先前开发的ToxProfiler工具和已发布的脂肪变性不良结果途径的预测来整理潜在的MIE。大多数MIE是转录因子，我们通过挖掘TRRUST数据库收集了它们的目标基因。分析PFAS和PAH对脂肪变性机制的影响。我们对暴露于PFAS或PAH的雄性和雌性大鼠肝脏组织的高通量转录组测量进行了计算性MIE靶基因分析.结果表明，过氧化物酶体增殖物激活受体（PPAR）-α的靶标是最失调的，大多数基因被上调。此外，PFAS暴露破坏了几个脂质代谢基因，包括脂肪酸氧化基因的上调(Acadm，Acox1，Cpt2，Cyp4a1-3）和脂质转运基因（Apoa1，Apoa5，Pltp）的下调。我们还确定了具有性别特异性行为的多个基因。值得注意的是,与雌性大鼠相比，雄性大鼠的糖异生（Pck1）和胆汁酸合成（Cyp7a1）的限速基因特异性下调，而脂质合成的限速基因（Scd）显示出PFAS特异性上调。结果提示PPAR信号通路在PFAS诱导的大鼠脂质蓄积中起主要作用。一起,这些结果表明,PFAS暴露诱导性别特异性多因素机制,涉及糖异生和胆汁酸合成的限速基因,这可能导致脂肪变性不良结局途径的激活.
