Given the global abundance and environmental persistence, exposure of humans and (aquatic) animals to micro- and nanoplastics is unavoidable. Current evidence indicates that micro- and nanoplastics ...can be taken up by aquatic organism as well as by mammals. Upon uptake, micro- and nanoplastics can reach the brain, although there is limited information regarding the number of particles that reaches the brain and the potential neurotoxicity of these small plastic particles.Earlier studies indicated that metal and metal-oxide nanoparticles, such as gold (Au) and titanium dioxide (TiO
) nanoparticles, can also reach the brain to exert a range of neurotoxic effects. Given the similarities between these chemically inert metal(oxide) nanoparticles and plastic particles, this review aims to provide an overview of the reported neurotoxic effects of micro- and nanoplastics in different species and in vitro. The combined data, although fragmentary, indicate that exposure to micro- and nanoplastics can induce oxidative stress, potentially resulting in cellular damage and an increased vulnerability to develop neuronal disorders. Additionally, exposure to micro- and nanoplastics can result in inhibition of acetylcholinesterase activity and altered neurotransmitter levels, which both may contribute to the reported behavioral changes.Currently, a systematic comparison of the neurotoxic effects of different particle types, shapes, sizes at different exposure concentrations and durations is lacking, but urgently needed to further elucidate the neurotoxic hazard and risk of exposure to micro- and nanoplastics.
Neurotoxicity of pesticides Richardson, Jason R.; Fitsanakis, Vanessa; Westerink, Remco H. S. ...
Acta neuropathologica,
09/2019, Letnik:
138, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Pesticides are unique environmental contaminants that are specifically introduced into the environment to control pests, often by killing them. Although pesticide application serves many important ...purposes, including protection against crop loss and against vector-borne diseases, there are significant concerns over the potential toxic effects of pesticides to non-target organisms, including humans. In many cases, the molecular target of a pesticide is shared by non-target species, leading to the potential for untoward effects. Here, we review the history of pesticide usage and the neurotoxicity of selected classes of pesticides, including insecticides, herbicides, and fungicides, to humans and experimental animals. Specific emphasis is given to linkages between exposure to pesticides and risk of neurological disease and dysfunction in humans coupled with mechanistic findings in humans and animal models. Finally, we discuss emerging techniques and strategies to improve translation from animal models to humans.
Background/objective: Polybrominated diphenyl ethers (PBDEs) and their hydroxylated (OH-) or methoxylated forms have been detected in humans. Because this raises concern about adverse effects on the ...developing brain, we reviewed the scientific literature on these mechanisms. Data synthesis: Many rodent studies reported behavioral changes after developmental, neonatal, or adult exposure to PBDEs, and other studies documented subtle structural and functional alterations in brains of PBDE-exposed animals. Functional effects have been observed on synaptic plasticity and the glutamate— nitric oxide— cyclic guanosine monophosphate pathway. In the brain, changes have been observed in the expression of genes and proteins involved in synapse and axon formation, neuronal morphology, cell migration, synaptic plasticity, ion channels, and vesicular neurotransmitter release. Cellular and molecular mechanisms include effects on neuronal viability (via apoptosis and oxidative stress), neuronal differentiation and migration, neurotransmitter release/uptake, neurotransmitter receptors and ion channels, calcium (Ca²⁺ ) homeostasis, and intracellular signaling pathways. Discussion: Bioactivation of PBDEs by hydroxylation has been observed for several endocrine end points. This has also been observed for mechanisms related to neurodevelopment, including binding to thyroid hormone receptors and transport proteins, disruption of Ca²⁺ homeostasis, and modulation of GABA and nicotinic acetylcholine receptor function Conclusions: The increased hazard for developmental neurotoxicity by hydroxylated (OH-) PBDEs compared with their parent congeners via direct neurotoxicity and thyroid disruption clearly warrants further investigation into a ) the role of oxidative metabolism in producing active metabolites of PBDEs and their impact on brain development; b) concentrations of parent and OH-PBDEs in the brain; and c) interactions between different environmental contaminants during exposure to mixtures, which may increase neurotoxicity.
•hiPSC-derived models develop into networks with spontaneous activity and bursting.•hiPSC- derived models containing astrocytes exhibit synchronized activity.•Co-cultures can be modulated with ...seizurogenic compounds and neurotoxicants.•Inhibitory and excitatory neuron ratio may influence the chemical sensitivity.•hiPSC-derived models may already be used as prioritization tool in toxicity testing.
Neurotoxicity testing still relies on ethically debated, expensive and time consuming in vivo experiments, which are unsuitable for high-throughput toxicity screening. There is thus a clear need for a rapid in vitro screening strategy that is preferably based on human-derived neurons to circumvent interspecies translation. Recent availability of commercially obtainable human induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes holds great promise in assisting the transition from the current standard of rat primary cortical cultures to an animal-free alternative.
We therefore composed several hiPSC-derived neuronal models with different ratios of excitatory and inhibitory neurons in the presence or absence of astrocytes. Using immunofluorescent stainings and multi-well micro-electrode array (mwMEA) recordings we demonstrate that these models form functional neuronal networks that become spontaneously active. The differences in development of spontaneous neuronal activity and bursting behavior as well as spiking patterns between our models confirm the importance of the presence of astrocytes. Preliminary neurotoxicity assessment demonstrates that these cultures can be modulated with known seizurogenic compounds, such as picrotoxin (PTX) and endosulfan, and the neurotoxicant methylmercury (MeHg). However, the chemical-induced effects on different parameters for neuronal activity, such as mean spike rate (MSR) and mean burst rate (MBR), may depend on the ratio of inhibitory and excitatory neurons. Our results thus indicate that hiPSC-derived neuronal models must be carefully designed and characterized prior to large-scale use in neurotoxicity screening.
The use of new psychoactive substances (NPS) is increasing and currently >600 NPS have been reported. However, limited information on neuropharmacological and toxicological effects of NPS is ...available, hampering risk characterization.
We reviewed the literature on the in vitro neuronal modes of action to obtain effect fingerprints of different classes of illicit drugs and NPS. The most frequently reported NPS were selected for review: cathinones (MDPV, α-PVP, mephedrone, 4-MEC, pentedrone, methylone), cannabinoids (JWH-018), (hallucinogenic) phenethylamines (4-fluoroamphetamine, benzofurans (5-APB, 6-APB), 2C-B, NBOMes (25B-NBOMe, 25C-NBOMe, 25I-NBOMe)), arylcyclohexylamines (methoxetamine) and piperazine derivatives (mCPP, TFMPP, BZP).
Our effect fingerprints highlight the main modes of action for the different NPS studied, including inhibition and/or reversal of monoamine reuptake transporters (cathinones and non-hallucinogenic phenethylamines), activation of 5-HT2receptors (hallucinogenic phenethylamines and piperazines), activation of cannabinoid receptors (cannabinoids) and inhibition of NDMA receptors (arylcyclohexylamines). Importantly, we identified additional targets by relating reported effect concentrations to the estimated human brain concentrations during recreational use. These additional targets include dopamine receptors, α- and β-adrenergic receptors, GABAAreceptors and acetylcholine receptors, which may all contribute to the observed clinical symptoms following exposure.
Additional data is needed as the number of NPS continues to increase. Also, the effect fingerprints we have obtained are still incomplete and suffer from a large variation in the reported effects and effect sizes. Dedicated in vitro screening batteries will aid in complementing specific effect fingerprints of NPS. These fingerprints can be implemented in the risk assessments of NPS that are necessary for eventual control measures to reduce Public Health risks.
Abstract Brominated flame retardants (BFRs) are widely used chemicals that prevent or slow the onset and spreading of fire. Unfortunately, many of these compounds pose serious threats for human ...health and the environment, indicating an urgent need for safe(r) and less persistent alternative flame retardants (AFRs). As previous research identified the nervous system as a sensitive target organ, the neurotoxicity of past and present flame retardants is reviewed. First, an overview of the neurotoxicity of BFRs in humans and experimental animals is provided, and some common in vitro neurotoxic mechanisms of action are discussed. The combined epidemiological and toxicological studies clearly underline the need for replacing BFRs. Many potentially suitable AFRs are already in use, despite the absence of a full profile of their environmental behavior and toxicological properties. To prioritize the suitability of some selected halogenated and non-halogenated organophosphorous flame retardants and inorganic halogen-free flame retardants, the available neurotoxic data of these AFRs are discussed. The suitability of the AFRs is rank-ordered and combined with human exposure data (serum concentrations, breast milk concentrations and house dust concentrations) and physicochemical properties (useful to predict e.g. bioavailability and persistence in the environment) for a first semi-quantitative risk assessment of the AFRs. As can be concluded from the reviewed data, several BFRs and AFRs share some neurotoxic effects and modes of action. Moreover, the available neurotoxicity data indicate that some AFRs may be suitable substitutes for BFRs. However, proper risk assessment is hampered by an overall scarcity of data, particularly regarding environmental persistence, human exposure levels, and the formation of breakdown products and possible metabolites as well as their toxicity. Until these data gaps in environmental behavioral and toxicological profiles are filled, large scale use of these chemicals should be cautioned.
Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) and polybrominated diphenyl ethers (PBDEs) are environmental pollutants that exert neurodevelopmental and neurobehavioral effects in vivo in ...humans and animals. Acute in vitro neurotoxic effects include changes in cell viability, oxidative stress, and basal intracellular calcium levels. Though these acute cellular effects could partly explain the observed in vivo effects, other mechanisms, such as effects on calcium influx and neurotransmitter receptor function, likely contribute to the disturbance in neurotransmission. This concise review combines in vitro data on cell viability, oxidative stress and basal calcium levels with recent data that clearly demonstrate that (hydroxylated) PCBs and (hydroxylated) PBDEs can exert acute effects on voltage-gated Ca²⁺ channels as well as on excitatory and inhibitory neurotransmitter receptors in vitro. These novel mechanisms of action are shared by NDL-PCBs, OH-PBDEs, and some other persistent organic pollutants, such as tetrabromobisphenol-A, and could have profound effects on neurodevelopment, neurotransmission, and neurobehavior in vivo.
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) approach can be used as an in vitro alternative for screening of marine neurotoxins potentially present in seafood. METHODS: This MEA approach utilizes rat cortical neurons comprising a wide range of ion channels/pumps and neurotransmitter receptors targeted by marine neurotoxins. We tested the effects of neurotoxic model compounds, pure marine neurotoxins, and extracts from contaminated seafood on neuronal activity of rat cortical neurons cultured on commercial 48‐well plates to increase throughput. CONCLUSION: We demonstrate that the MEA approach has a sensitivity of 88% (7/9 model compounds, 6/6 pure marine neurotoxins, and 2/2 marine neurotoxins present in seafood extracts were correctly identified) and a good reproducibility compared to existing in vitro alternatives. We therefore conclude that this MEA‐based approach could be a valuable tool for future food safety testing.
•TTX inhibits neuronal electrical activity in rat cortical cultures (IC50 ∼7nM).•TTX is equipotent in human iPSC-derived neurons (IC50 ∼10nM).•Our and literature data indicate that interspecies ...differences for TTX are limited.•Experimental animal data could be used to derive human acute reference dose (ARfD).•The ARfD amounts to 1.33μg/kg bw, or 200μg/kg TTX in shellfish.
Tetrodotoxin (TTX) is an extremely toxic marine neurotoxin. TTX inhibits voltage-gated sodium channels, resulting in a potentially lethal inhibition of neurotransmission. Despite numerous intoxications in Asia and Europe, limited (human) toxicological data are available for TTX. Additionally, the degree of interspecies differences for TTX is not well established, hampering the use of available (animal) data for human risk assessment and establishing regulatory limits for TTX concentrations in (shell)fish.
We therefore used micro-electrode array (MEA) recordings as an integrated measure of neurotransmission to demonstrate that TTX inhibits neuronal electrical activity in both primary rat cortical cultures and human-induced pluripotent stem cell (hIPSC)-derived iCell® neurons in co-culture with hIPSC-derived iCell® astrocytes, with IC50 values of 7 and 10nM, respectively.
From these data combined with LD50 values and IC50 concentrations of voltage-gated sodium channels derived from literature it can be concluded that interspecies differences are limited for TTX. Consequently, we used experimental animal data to derive a human acute reference dose of 1.33μg/kg body weight, which corresponds to maximum concentration of TTX in shellfish of 200μg/kg.
Abstract
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 GABA
A
receptor in neuronal function, we investigated acute effects of PFAS on this receptor and on spontaneous neuronal network activity. PFOS (Lowest Observed Effect Concentration (LOEC) 0.1 µM) and PFOA (LOEC 1 µM) inhibited the GABA-evoked current and acted as non-competitive human GABA
A
receptor antagonists. Network activity of rat primary cortical cultures increased following exposure to PFOS (LOEC 100 µM). However, exposure of networks of human induced pluripotent stem cell (hiPSC)-derived neurons decreased neuronal activity. The higher sensitivity of the α
1
β
2
γ
2L
GABA
A
receptor for PFAS as compared to neuronal networks suggests that PFAS have additional mechanisms of action, or that compensatory mechanisms are at play. Differences between rodent and hiPSC-derived neuronal networks highlight the importance of proper model composition. LOECs for PFAS on GABA
A
receptor and neuronal activity reported here are within or below the range found in blood levels of occupationally exposed humans. For PFOS, LOECs are even within the range found in human serum and plasma of the general population, suggesting a clear neurotoxic risk.
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