Comparative hepatotoxicity of novel lithium bis(trifluoromethanesulfonyl)imide (LiTFSI, ie. HQ-115) and legacy Perfluorooctanoic acid (PFOA) in male mice: Insights into epigenetic mechanisms and pathway-specific responses

• Published in: Environment international 2024-03, Vol.185, p.108556-108556, Article 108556
• Main Authors: Sands, Mia, Zhang, Xing, gal, Arnon, Laws, Mary, Spinella, Michael, Erdogan, Zeynep-Madak, Irudayaraj, Joseph
• Format: Article
• Language: English
• Subjects: Animals; Caprylates - toxicity; Chemical and Drug Induced Liver Injury - metabolism; DNA methylation; Epigenesis, Genetic; Fluorocarbons - toxicity; Hepatotoxicity; Hydrocarbons, Fluorinated; Imides; Lipid metabolism; Lithium - metabolism; Lithium - pharmacology; Lithium bis(trifluoromethanesulfonyl)imide (LiTFSI or HQ-115); Liver; Male; Mice; Perfluorooctanoic Acid (PFOA); PFAS
• ISSN: 0160-4120; 1873-6750
• DOI: 10.1016/j.envint.2024.108556

•LiTFSI (HQ-115), an emerging PFAS used in energy applications, exhibits distinct hepatotoxicity compared to the legacy PFOA.•RRBS-seq analysis reveals different DNA methylation patterns between acute and chronic exposure for both LiTFSI and PFOA.•PPARα, a crucial transcription factor, is upregulated in both exposures, with downstream genes indicating potential oxidative damage.•Epigenetic toxicity can provide critical information on disease mechanisms and biomarkers.•There is a need for comprehensive health risk assessment of emerging PFAS. Lithium Bis(trifluoromethanesulfonyl)imide (LiTFSI ie. HQ-115), a polymer electrolyte used in energy applications, has been detected in the environment, yet its health risks and environmental epigenetic effects remain unknown. This study aims to unravel the potential health risks associated with LiTFSI, investigate the role of DNA methylation-induced toxic mechanisms in its effects, and compare its hepatotoxic impact with the well-studied Perfluorooctanoic Acid (PFOA). Using a murine model, six-week-old male CD1 mice were exposed to 10 and 20 mg/kg/day of each chemical for 14 days as 14-day exposure and 1 and 5 mg/kg/day for 30 days as 30-day exposure. Results indicate that PFOA exposure induced significant hepatotoxicity, characterized by liver enlargement, and elevated serum biomarkers. In contrast, LiTFSI exposure showed lower hepatotoxicity, accompanied by mild liver injuries. Despite higher bioaccumulation of PFOA in serum, LiTFSI exhibited a similar range of liver concentrations compared to PFOA. Reduced Representative Bisulfite Sequencing (RRBS) analysis revealed distinct DNA methylation patterns between 14-day and 30-day exposure for the two compounds. Both LiTFSI and PFOA implicated liver inflammatory pathways and lipid metabolism. Transcriptional results showed that differentially methylated regions in both exposures are enriched with cancer/disease-related motifs. Furthermore, Peroxisome proliferator-activated receptor alpha (PPARα), a regulator of lipid metabolism, was upregulated in both exposures, with downstream genes indicating potential oxidative damages. Overall, LiTFSI exhibits distinct hepatotoxicity profiles, emphasizing the need for comprehensive assessment of emerging PFAS compounds.