Effects on and transfer across the blood-brain barrier in vitro—Comparison of organic and inorganic mercury species

BMC Pharmacology and Toxicology, Dec 2016

Background Transport of methylmercury (MeHg) across the blood-brain barrier towards the brain side is well discussed in literature, while ethylmercury (EtHg) and inorganic mercury are not adequately characterized regarding their entry into the brain. Studies investigating a possible efflux out of the brain are not described to our knowledge. Methods This study compares, for the first time, effects of organic methylmercury chloride (MeHgCl), EtHg-containing thiomersal and inorganic Hg chloride (HgCl 2 ) on as well as their transfer across a primary porcine in vitro model of the blood-brain barrier. Results With respect to the barrier integrity, the barrier model exhibited a much higher sensitivity towards HgCl 2 following basolateral incubation (brain-facing side) as compared to apical application (blood-facing side). These HgCl 2 induced effects on the barrier integrity after brain side incubation are comparable to that of the organic species, although MeHgCl and thiomersal exerted much higher cytotoxic effects in the barrier building cells. Hg transfer rates following exposure to organic species in both directions argue for diffusion as transfer mechanism. Inorganic Hg application surprisingly resulted in a Hg transfer out of the brain-facing compartment. Conclusions In case of MeHgCl and thiomersal incubation, mercury crossed the barrier in both directions, with a slight accumulation in the basolateral, brain-facing compartment, after simultaneous incubation in both compartments. For HgCl 2 , our data provide first evidence that the blood-brain barrier transfers mercury out of the brain.

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Effects on and transfer across the blood-brain barrier in vitro—Comparison of organic and inorganic mercury species

Lohren et al. BMC Pharmacology and Toxicology Effects on and transfer across the blood- brain barrier in vitro-Comparison of organic and inorganic mercury species Hanna Lohren 0 Julia Bornhorst 0 Romy Fitkau 0 Gabriele Pohl 0 Hans-Joachim Galla 1 Tanja Schwerdtle 0 0 Department of Food Chemistry, Institute of Nutritional Science, Univeristy of Potsdam , Potsdam , Germany 1 Institute of Biochemistry, University of Muenster , Muenster , Germany Background: Transport of methylmercury (MeHg) across the blood-brain barrier towards the brain side is well discussed in literature, while ethylmercury (EtHg) and inorganic mercury are not adequately characterized regarding their entry into the brain. Studies investigating a possible efflux out of the brain are not described to our knowledge. Methods: This study compares, for the first time, effects of organic methylmercury chloride (MeHgCl), EtHg-containing thiomersal and inorganic Hg chloride (HgCl2) on as well as their transfer across a primary porcine in vitro model of the blood-brain barrier. Results: With respect to the barrier integrity, the barrier model exhibited a much higher sensitivity towards HgCl2 following basolateral incubation (brain-facing side) as compared to apical application (blood-facing side). These HgCl2 induced effects on the barrier integrity after brain side incubation are comparable to that of the organic species, although MeHgCl and thiomersal exerted much higher cytotoxic effects in the barrier building cells. Hg transfer rates following exposure to organic species in both directions argue for diffusion as transfer mechanism. Inorganic Hg application surprisingly resulted in a Hg transfer out of the brain-facing compartment. Conclusions: In case of MeHgCl and thiomersal incubation, mercury crossed the barrier in both directions, with a slight accumulation in the basolateral, brain-facing compartment, after simultaneous incubation in both compartments. For HgCl2, our data provide first evidence that the blood-brain barrier transfers mercury out of the brain. Organic mercury; Inorganic mercury; Methylmercury; Thiomersal; Mercuric mercury; In vitro blood-brain barrier model - Background Mercury (Hg) is present in the environment due to both natural sources and anthropogenic activity. It exists as elemental Hg as well as inorganic and organic compounds, all incorporating different toxicological properties [1, 2]. Human exposure to organic species mainly results from the consumption of contaminated fish or seafood in the form of methylmercury (MeHg), the most frequently occurring organic species in the aquatic food chain [3]. The use of the ethylmercury (EtHg) containing preservative thiomersal in medical preparations, including vaccines, represents a nondietary route of human exposure towards organic Hg species [4]. In contaminated terrestrial food, Hg is mainly present as inorganic Hg [2]. In 2012, in accordance to the Joint FAO/WHO Expert Committee on Food Additives (JECFA) [2] the European Food Safety Authority (EFSA) Panel on Contaminants in the Food Chain established a tolerable weekly intake (TWI) of 4 μg/kg body weight (b.w.) for inorganic Hg [5]. Based on new epidemiological data, the EFSA Panel reevaluated for MeHg the provisional tolerable weekly intake (PTWI) of 1.6 μg/kg b.w. (JECFA [6]) and established a TWI of 1.3 μg/kg b.w.. High fish consumers may exceed this TWI by up to six fold [5]. The central nervous system (CNS) represents the major target organ of organic Hg species exposure [7]. Thiomersal shows a higher or at least similar toxicity compared to MeHg in brain associated cells in vitro (e.g. [8, 9]). However, the toxic potential of MeHg under in vivo conditions © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. seems to be higher, which might be a consequence of different disposition kinetics [10]. The transport of MeHg across the blood-brain barrier to the brain side is well described in literature, while EtHg and inorganic Hg are not adequately characterized regarding their entry into the brain. Based on in vitro as well as in vivo studies an active transport mechanism of MeHg as a cysteine complex (MeHg-S-Cys) across the blood-brain barrier via the L-type neutral amino acid transport (LAT) system has been proposed [11–14]. It has to be noted that the transport of MeHg across the blood-brain barrier involves both, uptake into and efflux from brain endothelial cel (...truncated)


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Hanna Lohren, Julia Bornhorst, Romy Fitkau, Gabriele Pohl, Hans-Joachim Galla, Tanja Schwerdtle. Effects on and transfer across the blood-brain barrier in vitro—Comparison of organic and inorganic mercury species, BMC Pharmacology and Toxicology, 2016, pp. 63, 17, DOI: 10.1186/s40360-016-0106-5