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
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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
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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)