Abstract
Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids (AsLs) occurring in fish and edible algae, possess a substantial neurotoxic potential in fully differentiated human brain cells. Previous in vivo studies indicating that AsHCs cross the blood–brain barrier of the fruit fly Drosophila melanogaster raised the question whether AsLs could also cross the vertebrate blood–brain barrier (BBB). In the present study, we investigated the impact of several representatives of AsLs (AsHC 332, AsHC 360, AsHC 444, and two arsenic-containing fatty acids, AsFA 362 and AsFA 388) as well as of their metabolites (thio/oxo-dimethylpropionic acid, dimethylarsinic acid) on porcine brain capillary endothelial cells (PBCECs, in vitro model for the blood–brain barrier). AsHCs exerted the strongest cytotoxic effects of all investigated arsenicals as they were up to fivefold more potent than the toxic reference species arsenite (iAsIII). In our in vitro BBB-model, we observed a slight transfer of AsHC 332 across the BBB after 6 h at concentrations that do not affect the barrier integrity. Furthermore, incubation with AsHCs for 72 h led to a disruption of the barrier at sub-cytotoxic concentrations. The subsequent immunocytochemical staining of three tight junction proteins revealed a significant impact on the cell membrane. Because AsHCs enhance the permeability of the in vitro blood–brain barrier, a similar behavior in an in vivo system cannot be excluded. Consequently, AsHCs might facilitate the transfer of accompanying foodborne toxicants into the brain.
Similar content being viewed by others
Abbreviations
- AsHC:
-
Arsenic-containing hydrocarbon
- AsFA:
-
Arsenic-containing fatty acid
- AsL:
-
Arsenolipid
- DMAV :
-
Dimethylarsinic acid
- iAsIII :
-
Arsenite
- oxo-DMAPr:
-
Oxo-dimethylarsenopropanoic acid
- PBCEC:
-
Porcine brain capillary endothelial cell
- TEER:
-
Transendothelial electrical resistance
- thio-DMAPr:
-
Thio-dimethylarsenopropanoic acid
References
Bornhorst J, Ebert F, Hartwig A et al (2010) Manganese inhibits poly(ADP-ribosyl)ation in human cells: a possible mechanism behind manganese-induced toxicity? J Environ Monit 12:2062. doi:10.1039/c0em00252f
Bornhorst J, Wehe CA, Huwel S et al (2012) Impact of manganese on and transfer across blood–brain and blood–cerebrospinal fluid barrier in vitro. J Biol Chem 287:17140–17151. doi:10.1074/jbc.M112.344093
Cullen WR, Reimer KJ (1989) Arsenic speciation in the environment. Chem Rev 89:713–764. doi:10.1021/cr00094a002
EFSA (2010) European Food Safety Authority—Panel on Contaminants in the Food Chain (CONTAM); scientific opinion on arsenic in food. EFSA J 2009(7):1–199
Francesconi KA, Edmonds JS (1996) Arsenic and marine organisms. Adv Inorg Chem 44:147–189. doi:10.1016/S0898-8838(08)60130-0
Franke H, Galla H-J, Beuckmann CT (1999) An improved low-permeability in vitro-model of the blood–brain barrier: transport studies on retinoids, sucrose, haloperidol, caffeine and mannitol. Brain Res 818:65–71. doi:10.1016/S0006-8993(98)01282-7
García-Salgado S, Raber G, Raml R et al (2012) Arsenosugar phospholipids and arsenic hydrocarbons in two species of brown macroalgae. Environ Chem 9:63. doi:10.1071/EN11164
IARC (2012) IARC monographs on the evaluation of carcinogenic risks to humans, vol 100 C, arsenic, metals, fibres, and dusts: this publication represents the views and expert opinions of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, which met in Lyon, 17–24 March 2009. IARC, Lyon
Khan M, Francesconi KA (2016) Preliminary studies on the stability of arsenolipids: implications for sample handling and analysis. J Environ Sci. doi:10.1016/j.jes.2016.04.004
Marschall TA, Bornhorst J, Kuehnelt D, Schwerdtle T (2016) Differing cytotoxicity and bioavailability of selenite, methylselenocysteine, selenomethionine, selenosugar 1 and trimethylselenonium ion and their underlying metabolic transformations in human cells. Mol Nutr Food Res 60:2622–2632. doi:10.1002/mnfr.201600422
Meyer S, Matissek M, Müller SM et al (2014a) In vitro toxicological characterisation of three arsenic-containing hydrocarbons. Metallomics 6:1023. doi:10.1039/c4mt00061g
Meyer S, Schulz J, Jeibmann A et al (2014b) Arsenic-containing hydrocarbons are toxic in the in vivo model Drosophila melanogaster. Metallomics 6:2010–2014. doi:10.1039/C4MT00249K
Meyer S, Raber G, Ebert F et al (2015a) In vitro toxicological characterisation of arsenic-containing fatty acids and three of their metabolites. Toxicol Res. doi:10.1039/C5TX00122F
Meyer S, Raber G, Ebert F et al (2015b) Arsenic-containing hydrocarbons and arsenic-containing fatty acids: transfer across and presystemic metabolism in the Caco-2 intestinal barrier model. Mol Nutr Food Res 59:2044–2056. doi:10.1002/mnfr.201500286
Niehoff A-C, Schulz J, Soltwisch J et al (2016) Imaging by elemental and molecular mass spectrometry reveals the uptake of an arsenolipid in the brain of Drosophila melanogaster. Anal Chem 88:5258–5263. doi:10.1021/acs.analchem.6b00333
Raab A, Newcombe C, Pitton D et al (2013) Comprehensive analysis of lipophilic arsenic species in a brown alga (Saccharina latissima). Anal Chem 85:2817–2824. doi:10.1021/ac303340t
Repetto G, del Peso A, Zurita JL (2008) Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nat Protoc 3:1125–1131. doi:10.1038/nprot.2008.75
Rodriguez VM, Del Razo LM, Limón-Pacheco JH et al (2005) Glutathione reductase inhibition and methylated arsenic distribution in Cd1 mice brain and liver. Toxicol Sci 84:157–166. doi:10.1093/toxsci/kfi057
Sandermann H (1978) Regulation of membrane enzymes by lipids. Biochim Biophys Acta BBA Rev Biomembr 515:209–237. doi:10.1016/0304-4157(78)90015-1
Schmeisser E, Goessler W, Francesconi KA (2006a) Human metabolism of arsenolipids present in cod liver. Anal Bioanal Chem 385:367–376. doi:10.1007/s00216-006-0401-x
Schmeisser E, Rumpler A, Kollroser M et al (2006b) Arsenic fatty acids are human urinary metabolites of arsenolipids present in cod liver. Angew Chem Int Ed 45:150–154. doi:10.1002/anie.200502706
Sele V, Sloth JJ, Lundebye A-K et al (2012) Arsenolipids in marine oils and fats: a review of occurrence, chemistry and future research needs. Food Chem 133:618–630. doi:10.1016/j.foodchem.2012.02.004
Sikkema J, de Bont JA, Poolman B (1995) Mechanisms of membrane toxicity of hydrocarbons. Microbiol Rev 59:201–222
Su C-K, Yang C-H, Lin C-H, Sun Y-C (2014) In-vivo evaluation of the permeability of the blood–brain barrier to arsenicals, molybdate, and methylmercury by use of online microdialysis-packed minicolumn-inductively coupled plasma mass spectrometry. Anal Bioanal Chem 406:239–247. doi:10.1007/s00216-013-7429-5
Taleshi MS, Jensen KB, Raber G et al (2008) Arsenic-containing hydrocarbons: natural compounds in oil from the fish capelin, Mallotus villosus. Chem Commun. doi:10.1039/b808049f
Taleshi MS, Seidler-Egdal RK, Jensen KB et al (2014) Synthesis and characterization of arsenolipids: naturally occurring arsenic compounds in fish and algae. Organometallics 33:1397–1403. doi:10.1021/om4011092
van Meer G, Simons K (1986) The function of tight junctions in maintaining differences in lipid composition between the apical and the basolateral cell surface domains of MDCK cells. EMBO J 5:1455–1464
Viczek SA, Jensen KB, Francesconi KA (2016) Arsenic-containing Phosphatidylcholines: a new group of Arsenolipids discovered in Herring Caviar. Angew Chem 128:5345–5348. doi:10.1002/ange.201512031
WHO (2011) World Health Organization—guidelines for drinking-water quality, 4th edn. World Health Organization, Geneva
Winckler J (1973) Vital staining of lysosomes and other cell organelles of the rat with neutral red. Prog Histochem Cytochem 6:III-89. doi:10.1016/S0079-6336(74)80001-X
Witt B, Bornhorst J, Mitze H et al (2017a) Arsenolipids exert less toxicity in a human neuron astrocyte co-culture as compared to the respective monocultures. Metallomics. doi:10.1039/C7MT00036G
Witt B, Meyer S, Ebert F et al (2017b) Toxicity of two classes of arsenolipids and their water-soluble metabolites in human differentiated neurons. Arch Toxicol. doi:10.1007/s00204-017-1933-x
Xi S, Sun W, Wang F et al (2009) Transplacental and early life exposure to inorganic arsenic affected development and behavior in offspring rats. Arch Toxicol 83:549–556. doi:10.1007/s00204-009-0403-5
Acknowledgements
This work was supported by the Heinrich-Stockmeyer-Foundation, the German Research Foundation (DFG) Grant number SCHW903/10-1 and the Austrian Science Fund (FWF), Project number I2412-B21.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Müller, S.M., Ebert, F., Raber, G. et al. Effects of arsenolipids on in vitro blood-brain barrier model. Arch Toxicol 92, 823–832 (2018). https://doi.org/10.1007/s00204-017-2085-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-017-2085-8