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Archives of Toxicology

, Volume 92, Issue 5, pp 1751–1765 | Cite as

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

  • S. M. Müller
  • H. Finke
  • F. Ebert
  • J. F. Kopp
  • F. Schumacher
  • B. Kleuser
  • K. A. Francesconi
  • G. Raber
  • T. Schwerdtle
Molecular Toxicology

Abstract

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.

Keywords

Arsenolipids Gene expression Arsenic-containing hydrocarbons Global DNA methylation Arsenic speciation Metabolism 

Abbreviations

AsHC

Arsenic-containing hydrocarbon

AsFA

Arsenic-containing fatty acid

BER

Base excision repair

dC

2′-Deoxycytidine

hmdC

5-Hydroxymethyl-2′-deoxycytidine

iAsIII

Arsenite

mdC

5-Methyl-2′-deoxycytidine

NER

Nucleotide excision repair

RT-qPCR

Reverse transcription quantitative real-time polymerase chain reaction

Notes

Funding

This work was supported by the Heinrich-Stockmeyer Foundation, the German Research Foundation (DFG) Grant Number SCHW903/10 − 1, the Austrian Science Fund (FWF), Project Number I2412-B21, as well as by the European Regional Development Fund (EFRE) and the federal state Brandenburg.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

204_2018_2194_MOESM1_ESM.docx (933 kb)
Supplementary material 1 (DOCX 933 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • S. M. Müller
    • 1
    • 2
  • H. Finke
    • 1
  • F. Ebert
    • 1
  • J. F. Kopp
    • 1
  • F. Schumacher
    • 1
    • 3
  • B. Kleuser
    • 1
  • K. A. Francesconi
    • 4
  • G. Raber
    • 4
  • T. Schwerdtle
    • 1
  1. 1.Institute of Nutritional ScienceUniversity of PotsdamNuthetalGermany
  2. 2.Heinrich-Stockmeyer FoundationBad RothenfeldeGermany
  3. 3.Department of Molecular BiologyUniversity of Duisburg-EssenEssenGermany
  4. 4.Institute of Chemistry, NAWI GrazUniversity of GrazGrazAustria

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