Comparative Hepatotoxicity of a Novel Perfluoroalkyl Ether Sulfonic Acid, Nafion Byproduct 2 (H-PFMO2OSA), and Legacy Perfluorooctane Sulfonate (PFOS) in Adult Male Mice

Abstract

Nafion byproduct 2 (H-PFMO2OSA) has been detected in the environment, but little is known about its toxicities. To compare the hepatotoxicity of H-PFMO2OSA with legacy perfluorooctane sulfonate (PFOS), male adult mice were exposed to 0.2, 1, or 5 mg/kg/d of each chemical for 28 days. Results showed that, although H-PFMO2OSA liver and serum concentrations were lower than those of PFOS, the relative liver weight in the H-PFMO2OSA groups was significantly higher than that in the corresponding PFOS groups. In addition, the increase in alanine transaminase and aspartate aminotransferase activity was greater in the H-PFMO2OSA groups than in the PFOS groups. Reduced glutathione (GSH) content and glutathione reductase activity in the liver increased in the 1 and 5 mg/kg/d H-PFMO2OSA groups and in the 5 mg/kg/d PFOS group. Liver quantitative proteome analysis demonstrated that, similar to PFOS, H-PFMO2OSA caused lipid metabolism disorder, and most lipid metabolism-related differentially expressed proteins (DEPs) were controlled by peroxisome proliferator-activated receptor alpha (PPARα). Additionally, KEGG enrichment analysis highlighted changes in the GSH metabolism pathway after PFOS and H-PFMO2OSA exposure. Then, there were eight DEPs involved in the GSH metabolism pathway that mostly were upregulated after exposure to H-PFMO2OSA but not after exposure to PFOS. In conclusion, H-PFMO2OSA induced higher levels of liver damage and more serious GSH metabolism dysregulation compared to PFOS.

Kynurenic Acid Plays a Protective Role in Hepatotoxicity Induced by HFPO-DA in Male Mice

“…17,51 Notably, hepatomegaly is a common indicator of PFAS-induced hepatotoxicity. 5,46,52,53 According to the US EPA, the lowest observed adverse effect levels (LOAEL) for increased relative liver weights in male CD1 mice following gavage exposure to HFPO-DA are 3 mg/ kg/d (28 d) and 5 mg/kg/d (90 d). 41,54 These levels are higher than the LOAEL (0.5 mg/kg/d) observed in our study after 7 days of HFPO-DA exposure, suggesting a potential underestimation of HFPO-DA-induced liver toxicity.…”

“…The liver serves as a crucial metabolic organ and a primary target for PFAS, which can accumulate in hepatic tissue and induce hepatotoxicity. , Notably, hepatomegaly is a common indicator of PFAS-induced hepatotoxicity. ,,, According to the US EPA, the lowest observed adverse effect levels (LOAEL) for increased relative liver weights in male CD1 mice following gavage exposure to HFPO-DA are 3 mg/kg/d (28 d) and 5 mg/kg/d (90 d). , These levels are higher than the LOAEL (0.5 mg/kg/d) observed in our study after 7 days of HFPO-DA exposure, suggesting a potential underestimation of HFPO-DA-induced liver toxicity. Possible factors contributing to the higher LOAEL values for chronic HFPO-DA exposure may include variances in mouse strains used in experiments or an increased resilience to HFPO-DA in mice stemming from prolonged exposure, leading to an eventual recovery from acute hepatic damage.…”

“…Protein extraction, isolation, and blotting were performed according to our previous study. 46 The expression level of GAPDH was used as an internal reference. Details regarding antibodies are given in Table S1.…”

A putative adverse outcome network for neonatal mortality and lower birth weight in rodents: Applicability to per‐ and polyfluoroalkyl substances and relevance to human health

“…That hydro‐PS acid ranked low for PPARα agonism suggests that CAR, PXR and perhaps RXR may be the drivers for its toxicity in rodents. The finding that 28‐day exposure to hydro‐PS acid causes severe hepatomegaly, higher serum bile acids and elevated markers of liver damage in male mice (Wang et al, 2022, 2023), and liver inflammation and high serum bile acid metabolites in pregnant rats (Conley, Lambright, Evans, Medlock‐Kakaley, et al, 2021) suggests that maternal metabolic derangements could contribute to the developmental toxicity of hydro‐PS acid. The relationship of these findings to the developmental toxicity of PFAS remains to be elucidated.…”

Structure-Related Thyroid Disrupting Effect of Perfluorooctanesulfonate-like Substances in Zebrafish Larvae

“…The PFOS-like substances were designed to be less toxic in organisms, though our knowledge of their biosafety remains limited. So far, the vast majority of the research on the toxic effects of PFOS-like substances pertains to Cl-PFESAs, particularly 6:2 Cl-PFESA, which consistently suggests that 6:2 Cl-PFESA is potent to cause strong detrimental effects on endocrine functions (e.g., thyroidal and lipid steatosis) in organisms as PFOS, or even stronger. − The only study to look into the toxicity of Cl-PFOS reported its potential to elicit comparable hepatotoxicity to PFOS in zebrafish larvae . As the recently identified reductive transformation product of 6:2 Cl-PFESA, information about 6:2 H-PFESA is heavily sparse.…”