Regina G D M van Kleef

Regina G D M van Kleef
Utrecht University | UU · Institute for Risk Assessment Sciences (IRAS)

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67
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1,660
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Publications

Publications (67)
Article
Full-text available
Introduction The accidental ingestion of diluted household descaling products by infants is a phenomenon that poison control centers regularly encounter. Feeding infants with baby milk prepared with water from electric kettles still containing descaler is a common way of exposure. This study aimed to determine the risks related to ingestion of (dil...
Article
Full-text available
Neurotoxicity testing of chemicals, drug candidates, and environmental pollutants still relies on extensive in vivo studies that are very costly, time‐consuming, and ethically debated due to the large number of animals typically used. Currently, rat primary cortical cultures are widely used for in vitro neurotoxicity studies, as they closely resemb...
Article
Full-text available
There is a great need for antiviral drugs to treat enterovirus (EV) and rhinovirus (RV) infections , which can be severe and occasionally life-threatening. The conserved nonstructural protein 2C, which is an AAA+ ATPase, is a promising target for drug development. Here, we present a structure-activity relationship study of a previously identified c...
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Full-text available
Concerns about the neurotoxic potential of polyfluoroalkyl substances (PFAS) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) increase, although their neurotoxic mechanisms of action remain debated. Considering the importance of the GABAA receptor in neuronal function, we investigated acute effects of PFAS on this receptor...
Article
Wnt dependency and Lgr5 expression define multiple mammalian epithelial stem cell types. Under defined growth factor conditions, such adult stem cells (ASCs) grow as 3D organoids that recapitulate essential features of the pertinent epithelium. Here, we establish long-term expanding venom gland organoids from several snake species. The newly assemb...
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The prevalence and use of new psychoactive substances (NPS) is increasing and currently over 600 NPS exist. Many illicit drugs and NPS increase brain monoamine levels by inhibition and/or reversal of monoamine reuptake transporters (DAT, NET and SERT). This is often investigated using labor-intensive, radiometric endpoint measurements. We investiga...
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There is an increasing demand for in vitro test systems to detect neurotoxicity for use in chemical risk assessment. In this study, we evaluated the applicability of rat primary cortical cultures grown on multi-well micro-electrode arrays (mwMEAs) to detect effects of chronic 14-day exposure to structurally different insecticides or methylmercury o...
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Annual prevalence of the use of common illicit drugs and new psychoactive substances (NPS) is high, despite the often limited knowledge on the health risks of these substances. Recently, cortical cultures grown on multi-well microelectrode arrays (mwMEAs) have been used for neurotoxicity screening of chemicals, pharmaceuticals, and toxins with a hi...
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Exposure to 50-60 Hz extremely low frequency electromagnetic fields (ELF-EMFs) has increased considerably over the last decades. Several epidemiological studies suggested that ELF-EMF exposure is associated with adverse health effects, including neurotoxicity. However, these studies are debated as results are often contradictory and the possible un...
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Piperazine derivatives are a class of psychoactive substances applied in prescription medicines like antidepressants as well as in drugs of abuse. They are known to increase brain levels of catecholamines, likely via reversal of reuptake transporters. However, other mechanisms could also contribute to increased neurotransmitter levels, e.g., reduce...
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Scope: At the European level, detection of marine neurotoxins in seafood is still based on ethically debated and expensive in vivo rodent bioassays. The development of alternative methodologies for the detection of marine neurotoxins is therefore of utmost importance. We therefore investigated whether and to what extent a multielectrode array (MEA...
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Yearly, exposure to drugs of abuse results in ∼1 million emergency department visits in the US. In ∼50% of the visits, stimulant drugs like cocaine and amphetamine-like substances (e.g. 3,4-methylenedioxymethamphetamine (MDMA, the main active ingredient of ecstasy)) are involved, whereas in ∼60% multiple drugs are involved. These drugs induce highe...
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Brominated flame retardants (BFRs) are abundant persistent organic pollutants with well-studied toxicity. The toxicological and ecological concern associated with BFRs argues for replacement by safer alternatives. However, the (neuro)toxic potential of alternative halogen-free flame retardants (HFFRs) is unknown. Previous research identified the ne...
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Neurotoxicological data on the widely used brominated flame retardant tetrabromobisphenol-A (TBBPA) is limited. Since recent studies indicated that inhibitory GABA(A) and excitatory α(4)β(2) nicotinic acetylcholine (nACh) receptors are sensitive targets for persistent organic pollutants, we investigated the effects of TBBPA on these receptors, expr...
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The neurotoxic potential of non-dioxin-like polychlorinated biphenyls (NDL-PCBs) is characterized by disruption of presynaptic processes, including calcium homeostasis and neurotransmitter transport. Recently, using a limited set of congeners, we demonstrated that PCB28 and PCB52 can potentiate postsynaptic GABAA receptors. In the present study, ef...
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PCBs are still ubiquitous pollutants despite the ban on their industrial and commercial use. To date, risk characterization and assessment of non-dioxin-like PCBs (NDL-PCBs), especially with respect to neurotoxicity, is hampered by a lack of data. Therefore, the effects of six common NDL congeners (PCB28, 52, 101, 138, 153 and 180) on human GABA(A)...
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Ethylbenzene and para-xylene (p-xylene), but not the chemically closely related organic solvents ortho-xylene (o-xylene) and meta-xylene (m-xylene), are known to cause ototoxicity and irreversible hearing loss, though the underlying mechanisms are still unknown. In this study, effects of ethylbenzene and of p-, o-, and m-xylene on human heteromeric...
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Oxidative metabolism, resulting in the formation of hydroxylated polybrominated diphenyl ether (PBDE) metabolites, may enhance the neurotoxic potential of brominated flame retardants. Our objective was to investigate the effects of a hydroxylated metabolite of 2,2',4,4'-tetra-bromodiphenyl ether (BDE-47; 6-OH-BDE-47) on changes in the intracellular...
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Increasing environmental levels of brominated flame retardants raise concern about possible adverse effects, particularly through early developmental exposure. The objective of this research was to investigate neurodevelopmental mechanisms underlying previously observed behavioral impairments observed after neonatal exposure to polybrominated diphe...
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Effects of cholinergic drugs on human alpha4beta2 nicotinic acetylcholine receptors expressed in Xenopus oocytes have been investigated in electrophysiological and ligand binding experiments. Atropine, scopolamine, physostigmine, and tacrine combine potentiation of ion current induced by low concentrations of acetylcholine with inhibition of ion cu...
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Chronic and acute exposure to organophosphate (OP) pesticides may lead to persistent neurological and neurobehavioral effects, which cannot be explained by acetylcholinesterase (AChE) inhibition alone. It is suggested that other brain proteins are involved. Effects of commonly used organophosphate pesticides on rat neuronal alpha4beta2 nicotinic ac...
Article
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The mechanism by which carbamate pesticides inhibit rat alpha4beta2 nicotinic acetylcholine (ACh) receptors (nAChRs) expressed in Xenopus laevis oocytes has been investigated using the two-electrode voltage clamp technique. Carbaryl, S-ethyl N,N-dipropylthiocarbamate (EPTC), and fenoxycarb inhibit ACh-induced ion currents in a concentration-depende...
Article
Effects of commonly used carbamate pesticides on rat neuronal nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes have been investigated using the two-electrode voltage clamp technique. The potencies of these effects have been compared to the potencies of the carbamates to inhibit rat brain acetylcholinesterase. The potency order...
Article
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The effects of the acetylcholinesterase inhibitors physostigmine and tacrine on α4β2 and α4β4 subtypes of neuronal nicotinic acetylcholine (ACh) receptors, expressed in Xenopus laevis oocytes, have been investigated. In voltage-clamp experiments low concentrations of physostigmine and tacrine potentiate ion currents induced by low concentrations of...
Article
Species-specific agonist binding regions of nicotinic acetylcholine receptors (nAChR) were examined. Imidacloprid and physostigmine (Phy) selectively activated insect nAChR composed of Drosophila second alpha-like subunit (SAD) and chick β2, in contrast to rat α7 nAChR. The Phy-activated currents were α-bungarotoxin (α-BGT) sensitive, suggesting ac...
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Article
The effects of the carbamate physostigmine and of the organophosphates (OPs) parathion, paraoxon and phenyl saligenin cyclic phosphate (PSP) were examined on different subtypes of neuronal nicotinic acetylcholine receptors (nAChR). Stimulation with 1 mM ACh induced transient nicotinic inward currents in mouse N1E-115 and human SH-SYSY neuroblastoma...
Article
The effects of acetylcholine (ACh) and physostigmine (PHY) on thoracic ganglion neurons of Locusta migratoria were investigated using whole-cell and cell-attached voltage clamp. ACh activated whole-cell currents with variable amplitudes, time course and ion channel block between cells, suggesting differential expression of nicotinic acetylcholine r...
Article
Effects of selective and non-selective neurotoxic compounds on membrane currents mediated by nicotinic acetylcholine receptors (nAChR), natively expressed in cultured cells and artificially expressed in Xenopus oocytes, have been investigated in vitro using voltage clamp techniques. Mammalian neuronal nAChR in cultured mouse N1E-115 cells, muscle t...
Article
Among persistent neurotoxicants inorganic lead (Pb2+) is known to cause a variety of cellular effects associated with alterations in neuronal performance. Here we describe differential effects of Pb2+ on distinct subtypes of neuronal nicotinic acetylcholine receptors (nAChR) in Xenopus oocytes expressing various combinations of alpha and beta recep...
Article
In cultured mouse neuroblastoma N1E-115 cells, inorganic lead (Pb2+) affects inward currents induced by activation of neuronal type nicotinic acetylcholine receptors (nAChR) in a biphasic manner. At nanomolar concentrations a blocking action is observed, while at submillimolar concentrations this blocking effect is reversed, resulting in a U-shaped...
Article
Full-text available
The effects of nitromethylene heterocycle (NMH) and organophosphate (OP) insecticides were studied on nicotinic acetylcholine receptors (nAChR) in cultured cells of different species origin, in order to examine the selectivity of these compounds at the level of the target sites. In mouse muscle BC3H1, mouse NIE-115 and human SH-SY5Y neuroblastoma,...
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The direct effects of two organophosphates, parathion and paraoxon, on nicotinic and muscarinic acetylcholine receptors in cells from different species were investigated, by using the whole-cell voltage clamp technique. The effects of neuronal type nicotinic receptors in mouse N1E-115, human SH-SY5Y and locust thoracic ganglion cells, and on human...
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Effects of inorganic lead (Pb2+) on defined subtypes of neuronal nicotinic acetylcholine receptors have been investigated. Voltage clamp experiments have been performed on Xenopus oocytes expressing alpha 3 beta 2, alpha 3 beta 4 and alpha 4 beta 2 neuronal nicotinic acetylcholine receptor subunit combinations. In oocytes expressing the alpha 3 bet...
Article
1. Pb2+ affects neuronal nicotinic acetylcholine receptors (nAChR) in NIE-115 neuroblastoma cells in a dual manner. At nanomolar concentrations a blockade is observed, while at submillimolar concentrations this blocking effect is reversed. 2. The Xenopus oocyte expression system was used to examine whether the dual effect of Pb2+ is related to a di...
Article
1. The ability of various divalent metal ions to substitute for Ca2+ in activating distinct types of Ca2+-dependent K+ [K+(Ca2+] channels has been investigated in excised, inside-out membrane patches of human erthrocytes and of clonal N1E-115 mouse neuroblastoma cells using the patch clamp technique. The effects of the various metal ions have been...
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Effects of Pb and several other metal ions on various distinct types of voltage-, receptor- and Ca-activated ion channels have been investigated in cultured N1E-115 mouse neuroblastoma cells. Experiments were performed using the whole-cell voltage clamp and single-channel patch clamp techniques. External superfusion of nanomolar to submillimolar co...
Article
Ca(2+)-activated K+ [K(Ca)] channels were studied in excised patches of resting and activated human peripheral blood T lymphocytes. The K(Ca) channel had a single-channel conductance of 50 +/- 6 pS in symmetrical high-K+ solutions in the potential range of -100 to -10 mV and was inwardly rectifying at more depolarized potentials. The channel was se...
Article
In order to resolve single channel events underlying the 5-HT3 receptor-gated ion current in N1E-115 neuroblastoma cells patch clamp experiments have been performed on excised outside-out membrane patches under optimized experimental conditions. When the driving force for Na+ through the 5-HT3 receptor-gated ion channel is enhanced by raising the e...
Article
Mouse neuroblastoma cells of the clone N1E-115 express a variety of ion channels and receptors, including a number that is also involved in neurotransmission. Effects of Pb2+ on several of these ion channels have been investigated under experimental conditions that allow electrophysiological recording of membrane current carried by distinct types o...
Article
Using electrophysiological techniques, effects of neurotoxicants were studied on mammalian neuronal and endplate type nicotinic acetylcholine receptors (nAChR) in N1E-115 cells and in BC3H(1) cells, respectively, and insect nAChR in locust neurons. Neuronal nAChR are highly sensitive to inorganic lead (Pb(2+)). Between 1 nm and 3 mum-Pb(2+) the ACh...
Article
Effects of Cd2+, Co2+, Fe2+ and Mg2+ (1 microM and 100 microM) and Pb2+ (1 microM and 90 microM) on single-channel properties of the small-conductance (SK) and large-conductance (BK) Ca(2+)-activated K+ channels were investigated in inside-out patches of N1E-115 mouse neuroblastoma cells. Cd2+, Co2+ and Pb2+, but not Fe2+ and Mg2+, cause SK channel...
Article
Using the patch-clamp technique single-channel properties of Ca(2+)-activated K+ (CaK) channels were investigated in inside-out membrane patches of human erythrocytes. In a physiological K+ gradient (5 mM K+ externally: 150 mM K+ internally) the single CaK channel conductance is 15 pS in the membrane potential range of -40 to +40 mV. The channel op...
Article
Effects of Cd2+, Co2+, Pb2+, Fe2+ and Mg2+ (1-100 microM) on single-channel properties of the intermediate conductance Ca(2+)-activated K+ (CaK) channels were investigated in inside-out patches of human erythrocytes in a physiological K+ gradient. Cd2+, Co2+ and Pb2+, but not Fe2+ and Mg2+, were able to induce CaK channel openings. The potency of t...
Article
Effects of local anesthetics and anticonvulsants on the pyrethroid-modified sodium current in cultured mouse neuroblastoma cells have been investigated using the suction pipette voltage clamp technique. In the presence of 10 μM of the pyrethroid deltamethrin the sodium current consists of an enhanced peak current during membrane depolarization and...
Article
The effects of inorganic lead (Pb2+) on the ion currents mediated by (1) neuronal nicotinic acetylcholine (ACh) receptors, (2) serotonin 5-HT3 receptors, as well as (3) voltage-dependent Ca2+ and Na+ channels have been investigated in voltage clamped mouse neuroblastoma cells. The nicotinic ACh receptor-ion channel complex appeared more sensitive t...
Article
Superfusion with Pb2+ induces a slow, noninactivating and reversible inward current in voltage-clamped N1E-115 neuroblastoma cells. The amplitude of this inward current increases in the range of 1-200 microM Pb/+. Single-channel patch-clamp experiments have revealed that this inward current is mediated by discrete ion channels. Reversal potentials...
Article
The effects of the pyrethroids allethrin, 1R-cis-cyphenothrin, 1R-cis-fenfluthrin, and of the noninsecticidal isomer 1S-cis-fenfluthrin on neurotransmitter receptor-mediated membrane responses have been investigated in the mouse neuroblastoma cell line N1E-115 using electrophysiological methods. At a concentration of 10 μM, allethrin and 1R-cis-cyp...
Article
(1) The interaction of a series of pyrethroid insecticides with the Na+ channels in myelinated nerve fibres of the clawed frog, Xenopus laevis, was investigated using the voltage clamp technique. (2) Out of 11 pyrethroids 9 insecticidally active compounds induce a slowly decaying Na+ tail current on termination of a step depolarization, whereas the...

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