Exposure to GenX and Its Novel Analogs Disrupts Hepatic Bile Acid Metabolism in Male Mice

Abstract

Due to its wide usage and recent detection in environmental matrices, hexafluoropropylene oxide dimer acid (HFPO–DA, commercial name GenX) has attracted considerable attention. Here, we explored and compared the toxicity of GenX and its novel analogs with that of perfluorooctanoic acid (PFOA) to provide guidance on the structural design and optimization of novel alternatives to poly- and perfluoroalkyl substances (PFASs). Adult male BALB/c mice were continuously exposed to PFOA, GenX, perfluoro-2-methyl-3,6-dioxo-heptanoic acid (PFMO2HpA), and perfluoro-2-methyl-3,6,8-trioxo-nonanoic acid (PFMO3NA; 0, 0.4, 2, or 10 mg/kg/d) via oral gavage for 28 days. The PFOA, GenX, and PFMO3NA treatment groups showed an increase in relative liver weight, and bile acid metabolism was the most significantly affected pathway in all treatment groups, as shown via weighted gene coexpression network analysis. The highest total bile acid levels were observed in the 2 and 10 mg/kg/d PFMO3NA groups. The ratios of primary bile acids to all bile acids increased in the high-dose groups, while the ratios of secondary bile acids showed a downward trend. Thus, bile acid metabolism disorder may be a prominent adverse effect induced by exposure to GenX, its analogs, and PFOA. Results also showed that the hepatotoxicity of PFMO2HpA was lower than that of GenX, whereas the hepatotoxicity of PFMO3NA was stronger, suggesting that PFMO2HpA may be a potential alternative to GenX.

Vital Environmental Sources for Multitudinous Fluorinated Chemicals: New Evidence from Industrial Byproducts in Multienvironmental Matrices in a Fluorochemical Manufactory

“…Toxicological investigations have shown that 6:2 F-53B has potential bioaccumulation and endocrine disrupting effects, causing liver damage and activating the peroxisome proliferator-activated receptor pathway in the kidney. − This alternative was revealed to be even stronger biological toxicity than PFOS. HFPO-DA also exhibited hepatotoxicity comparable to PFOA, while 6:2 FTS showed clear bioaccumulation and moderate hepatotoxic effects. , The high mobility and adverse toxicological implications of short-chain potassium perfluorobutane sulfonic acid (PFBS) could result in important issues for health and the environment. , …”

Insights into the Dermal Absorption, Deposition, and Elimination of Poly- and Perfluoroalkyl Substances in Rats: The Importance of Skin Exposure

“…57 PFAS enrichment in the blood could activate the peroxisome proliferator-activated receptor (PPARα), thereby reducing Oatp expression and OATP activity. 57 Additionally, the activities of cytoplasmic proteins for binding with PFASs in hepatocytes, such as liver− fatty acid binding protein (L-FABP), 58 were disrupted at high doses of PFASs (hexafluoropropylene oxide dimer acid (HFPO-DA), 2−5 μg/g; PFOA, 3−20 μg/g), 59,60 which may explain the decreased transport efficiency from the blood to liver observed in the H group (2 μg/g PFOA).…”

Hydrogels and Hydrogel Nanocomposites: Enhancing Healthcare through Human and Environmental Treatment

“…[97] Disruption of hepatic bile acid metabolisms has recently been associated with exposure to a slew of organic pollutants, specifically GenX, its analogs, and PFAS. [98][99][100] The removal of these substances using bile acid sequestrants, or hypocholesterolemic agent-containing polymers, has gained popularity given their high experimental sorption efficiency. [96,[101][102][103] Some of these sequestrants include hydrogels such as Enterosgel and cellulose-based materials.…”