全氟烷基和多氟烷基物质(PFAS)是一大类氟化碳链,包括传统的PFAS,如全氟辛烷磺酸(PFOS),全氟辛酸(PFOA),全氟壬酸(PFNA),和全氟己烷磺酸盐(PFHxS)。这些化合物会引起不良的健康影响,包括肝毒性.传统PFAS(HFPO-DA(GenX))的潜在替代方案,HFPO4,HFPO-TA,F-53B,6:2FTSA,和6:2FTCA),以及PFAS制造的副产品(NafionBP2),越来越多地出现在环境中。这些新替代品的潜在危害鲜为人知。为了更好地了解PFAS分子靶标的多样性,我们对暴露于这些PFAS的小鼠肝脏中的基因表达变化进行了比较毒性基因组学分析,并将它们与PPARα的五种活化剂进行比较,许多PFAS的共同目标。使用分层聚类,途径分析,和预测性生物标志物,我们发现,大多数替代PFAS可调节与遗留PFAS重叠的分子靶标.测试的11种PFAS中只有三种没有明显激活PPARα(NafionBP2,6:2FTSA,和6:2FTCA)。预测性生物标志物显示,大多数PFAS(PFHxS,PFOA,全氟辛烷磺酸,PFNA,HFPO-TA,F-53B,HFPO4,NafionBP2)激活CAR。PFNA,PFHxS,PFOA,全氟辛烷磺酸,HFPO4,HFPO-TA,F-53B,NafionBP2和6:2FTSA抑制STAT5b,激活NRF2,并激活SREBP。碳链的长度之间没有明显的关系,头组的类型,或醚键的数量和转录组的变化。这项工作突出了传统和替代PFAS之间分子靶标的相似性。
Per- and poly-fluoroalkyl substances (PFAS) are a large class of fluorinated carbon chains that include legacy PFAS, such as perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexane sulfonate (PFHxS). These compounds induce adverse health effects, including hepatotoxicity. Potential alternatives to the legacy PFAS (HFPO-DA (GenX), HFPO4, HFPO-TA, F-53B, 6:2 FTSA, and 6:2 FTCA), as well as a byproduct of PFAS manufacturing (Nafion BP2), are increasingly being found in the environment. The potential hazards of these new alternatives are less well known. To better understand the diversity of molecular targets of the PFAS, we performed a comparative toxicogenomics analysis of the gene expression changes in the livers of mice exposed to these PFAS, and compared these to five activators of PPARα, a common target of many PFAS. Using hierarchical clustering, pathway analysis, and predictive biomarkers, we found that most of the alternative PFAS modulate molecular targets that overlap with legacy PFAS. Only three of the 11 PFAS tested did not appreciably activate PPARα (Nafion BP2, 6:2 FTSA, and 6:2 FTCA). Predictive biomarkers showed that most PFAS (PFHxS, PFOA, PFOS, PFNA, HFPO-TA, F-53B, HFPO4, Nafion BP2) activated CAR. PFNA, PFHxS, PFOA, PFOS, HFPO4, HFPO-TA, F-53B, Nafion BP2, and 6:2 FTSA suppressed
STAT5b, activated NRF2, and activated SREBP. There was no apparent relationship between the length of the carbon chain, type of head group, or number of ether linkages and the transcriptomic changes. This work highlights the similarities in molecular targets between the legacy and alternative PFAS.