Health & Environmental Research Online (HERO)


Print Feedback Export to File
5024252 
Journal Article 
Hepatotoxicity of perfluorooctanoic acid and two emerging alternatives based on a 3D spheroid model 
Sun, S; Guo, Hua; Wang, J; Dai, J 
2019 
Yes 
Environmental Pollution
ISSN: 0269-7491
EISSN: 1873-6424 
ELSEVIER SCI LTD 
OXFORD 
246 
955-962 
English 
Perfluorooctanoic acid (PFOA) toxicity is of considerable concern due to its wide application, environmental persistence, and bioaccumulation. In the current study, we used a scaffold-free three-dimensional (3D) spheroid model of mouse liver cells (AML12) to explore the toxicity of PFOA and emerging alternatives (HFPO-DA and PFO4DA). Comparing the short-term (24 and 72 h treatment) toxicity of PFOA between conventional 2D monolayer cells and 3D spheroids, we found that spheroids had higher EC50 values and lower ROS levels after treatment, indicating their greater resistance to PFOA. Cell viability (i.e., adenosine triphosphate (ATP) content and lactate dehydrogenase (LDH) leakage) and liver-specific function (i.e., albumin secretion) were stable in spheroids through 28 day of culture. However, under 100 and 200 μM-PFOA treatment for 28 day, ROS levels, LDH leakage, and caspase3/7 activity all increased significantly. As a sensitive parameter, ROS showed a significant increase at 21 day, even in the 50 μM-PFOA group. Consistent with the elevation of ROS and caspase3/7, the expressions of oxidative stress- and apoptosis-related genes, including Gsta2, Nqo1, Ho-1, caspase3, p53, and p21, were induced in dose- and time-dependent manners after PFOA exposure. The peroxisome proliferator-activated receptor alpha (PPARα) pathway was also activated after treatment, with significant induction of its target genes, Fabp4 and Scd1. Similar to PFOA, both HFPO-DA and PFO4DA activated the PPARα pathway, induced ROS levels, and initiated cell damage, though at a relatively lower extent than that of PFOA. Our results imply that the 3D spheroid model is a valuable tool in chronic toxicological studies. 
Spheroid; Perfluorooctanoic acid; Hepatotoxicity; HFPO-DA; PFO4DA 
PFAS
• Additional PFAS (formerly XAgency)
     Literature Search November 2019
          Other Sources
               Reference list review of included studies
     Screened Studies
          Excluded
               Exclude (TIAB)
• Expanded PFAS SEM (formerly PFAS 430)
     Litsearch: September 2019
          PubMed
     Not prioritized for screening
     Potassium perfluorooctanoate
     Sodium perfluorooctanoate
• PFAS 150
     Literature Search Update December 2020
          PubMed
          WOS
     Literature Search August 2019
          PubMed
          Web of Science
     Ammonium perfluoro-2-methyl-3-oxahexanoate
     Ammonium perfluorooctanoate
     Perfluoro(2-methyl-3-oxahexanoyl) fluoride
     Perfluoro-2-methyl-3-oxahexanoic acid
     Perfluorooctanoic acid
• PFAS Universe
     Data Source
          Web of Science
          Pubmed
          Screened Studies
               Excluded
                    Exclude (TIAB)
     Perfluoro(2-propoxypropanoate)
     Perfluoro-2-methyl-3-oxahexanoic acid
     Perfluoro-3,5,7,9-butaoxadecanoic acid
     Perfluorooctanoate
     Trifluoro(trifluoromethyl)oxirane
     Perfluorooctanoic acid
• PFNA
OW - HHRAB
• GenX Chemicals (CASRN 13252-13-6 and CASRN 62037-80-3)
     LitSearch GenX Ammonium Salt: Feb 2018 - Feb 2019
          WoS
• PFOA (335-67-1) and PFOS (1763-23-1)
     Literature Search Update (2013-2019)
          WOS