Arsenic-containing hydrocarbons: effects on gene expression, epigenetics, and biotransformation in HepG2 cells

• Published in: Archives of toxicology Vol. 92; no. 5; pp. 1751 - 1765
• Main Authors: Müller, S. M., Finke, H., Ebert, F., Kopp, J. F., Schumacher, F., Kleuser, B., Francesconi, K. A., Raber, G., Schwerdtle, T.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2018; Springer Nature B.V
• Subjects: Alcohols; Algae; Arsenic; Arsenic - pharmacokinetics; Arsenic - toxicity; Autophagy; Biomedical and Life Sciences; Biomedicine; Biotransformation; Cell death; Cell lines; Cellular stress response; Chromatography, High Pressure Liquid; Culture Media - analysis; Culture Media - chemistry; Cytosine; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - drug effects; DNA repair; DNA Repair - drug effects; DNA Repair - genetics; Dose-Response Relationship, Drug; Endonuclease; Energy levels; Environmental Health; Epigenesis, Genetic - drug effects; Epigenetics; Fatty acids; FEN1 protein; Gene expression; Gene Expression Regulation - drug effects; Hep G2 Cells; Hepatocytes; High-performance liquid chromatography; Humans; Hydrocarbons; Hydrocarbons - administration & dosage; Hydrocarbons - chemistry; Hydrocarbons - pharmacokinetics; Hydrocarbons - toxicity; Liquid chromatography; Liver; Mass spectrometry; Mass spectroscopy; Metabolites; Methyltransferase; Mode of action; Molecular Toxicology; Occupational Medicine/Industrial Medicine; Phagocytosis; Pharmacology/Toxicology; Spectrometry, Mass, Electrospray Ionization; Stability analysis; Subgroups; Tandem Mass Spectrometry; Toxicity; Xeroderma pigmentosum; Arsenic speciation; Gene expression; Metabolism; Arsenolipids; Global DNA methylation; Arsenic-containing hydrocarbons
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-018-2194-z

Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids found in fish and algae, elicit substantial toxic effects in various human cell lines and have a considerable impact on cellular energy levels. The underlying mode of action, however, is still unknown. The present study analyzes the effects of two AsHCs (AsHC 332 and AsHC 360) on the expression of 44 genes covering DNA repair, stress response, cell death, autophagy, and epigenetics via RT-qPCR in human liver (HepG2) cells. Both AsHCs affected the gene expression, but to different extents. After treatment with AsHC 360, flap structure-specific endonuclease 1 ( FEN1 ) as well as xeroderma pigmentosum group A complementing protein ( XPA ) and (cytosine-5)-methyltransferase 3A ( DNMT3A ) showed time- and concentration-dependent alterations in gene expression, thereby indicating an impact on genomic stability. In the subsequent analysis of epigenetic markers, within 72 h, neither AsHC 332 nor AsHC 360 showed an impact on the global DNA methylation level, whereas incubation with AsHC 360 increased the global DNA hydroxymethylation level. Analysis of cell extracts and cell media by HPLC–mass spectrometry revealed that both AsHCs were considerably biotransformed. The identified metabolites include not only the respective thioxo-analogs of the two AsHCs, but also several arsenic-containing fatty acids and fatty alcohols, contributing to our knowledge of biotransformation mechanisms of arsenolipids.