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chemical neurotoxicity

Ellen V S Hessel, Yvonne C M Staal, Aldert H Piersma
Developmental neurotoxicity entails one of the most complex areas in toxicology. Animal studies provide only limited information as to human relevance. A multitude of alternative models have been developed over the years, providing insights into mechanisms of action. We give an overview of fundamental processes in neural tube formation, brain development and neural specification, aiming at illustrating complexity rather than comprehensiveness. We also give a flavor of the wealth of alternative methods in this area...
March 12, 2018: Toxicology and Applied Pharmacology
Charles V Vorhees, Jenna N Sprowles, Samantha L Regan, Michael T Williams
High throughput screens for developmental neurotoxicity (DN) will facilitate evaluation of chemicals and can be used to prioritize those designated for follow-up. DN is evaluated under different guidelines. Those for drugs generally include peri- and postnatal studies and juvenile toxicity studies. For pesticides and commercial chemicals, when triggered, include developmental neurotoxicity studies (DNT) and extended one-generation reproductive toxicity studies. Raffaele et al. (2010) reviewed 69 pesticide DNT studies and found two of the four behavioral tests underperformed...
March 12, 2018: Toxicology and Applied Pharmacology
Kylie D Rock, Heather B Patisaul
PURPOSE OF REVIEW: With the incidence of neurodevelopmental disorders on the rise, it is imperative to identify and understand the mechanisms by which environmental contaminants can impact the developing brain and heighten risk. Here, we report on recent findings regarding novel mechanisms of developmental neurotoxicity and highlight chemicals of concern, beyond traditionally defined neurotoxicants. RECENT FINDINGS: The perinatal window represents a critical and extremely vulnerable period of time during which chemical insult can alter the morphological and functional trajectory of the developing brain...
March 13, 2018: Current Environmental Health Reports
Éverton L Vogt, Jorge F A Model, Anapaula S Vinagre
Organotins (OTs) are considered some of the most toxic chemicals introduced into aquatic environments by anthropogenic activities. They are widely used for agricultural and industrial purposes and as antifouling additives on boat hull's paints. Even though the use of OTs was banned in 2008, elevated levels of OTs can still be detected in aquatic environments. OTs' deleterious effects upon wildlife and experimental animals are well documented and include endocrine disruption, immunotoxicity, neurotoxicity, genotoxicity, and metabolic dysfunction...
2018: Frontiers in Endocrinology
Chang He, Karin English, Christine Baduel, Phong Thai, Paul Jagals, Robert S Ware, Yan Li, Xianyu Wang, Peter D Sly, Jochen F Mueller
In recent years, the production and usage volumes of organophosphate flame retardants (OPFRs) has increased substantially. Certain OPFRs are suspected reproductive toxins, carcinogenic, and neurotoxic. Insufficient information is available on human exposure pathways to these chemicals, particularly in Australia. We aim to assess the association between OPFR concentrations in the urine of children to environmental and behavioural risk factors. Concentrations of eight OPFRs and eleven metabolites were measured in the urine of 51 children, aged 3-29 months, in Southeast Queensland, Australia and compared to their behavioural and environmental risk factor data obtained by an online questionnaire...
March 8, 2018: Environmental Research
Magdalini Sachana, Alexandra Rolaki, Anna Bal-Price
The Adverse Outcome Pathways (AOPs) are designed to provide mechanistic understanding of complex biological systems and pathways of toxicity that result in adverse outcomes (AOs) relevant to regulatory endpoints. AOP concept captures in a structured way the causal relationships resulting from initial chemical interaction with biological target(s) (molecular initiating event) to an AO manifested in individual organisms and/or populations through a sequential series of key events (KEs), which are cellular, anatomical and/or functional changes in biological processes...
March 7, 2018: Toxicology and Applied Pharmacology
Maria Letizia Barreca, Nunzio Iraci, Silvia Biggi, Violetta Cecchetti, Emiliano Biasini
Prion diseases are associated with the conversion of the cellular prion protein (PrPC ), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrPSc ) that accumulates in brain tissues of affected individuals. PrPSc is a self-catalytic protein assembly capable of recruiting native conformers of PrPC , and causing their rearrangement into new PrPSc molecules. Several previous attempts to identify therapeutic agents against prion diseases have targeted PrPSc , and a number of compounds have shown potent anti-prion effects in experimental models...
March 7, 2018: Pathogens
Anna Bal-Price, Helena T Hogberg, Kevin M Crofton, Mardas Daneshian, Rex E FitzGerald, Ellen Fritsche, Tuula Heinonen, Susanne Hougaard Bennekou, Stefanie Klima, Aldert H Piersma, Magdalini Sachana, Timothy J Shafer, Andrea Terron, Florianne Monnet-Tschudi, Barbara Viviani, Tanja Waldmann, Remco H S Westerink, Martin F Wilks, Hilda Witters, Marie-Gabrielle Zurich, Marcel Leist
Multiple non-animal-based test methods have never been formally validated. In order to use such new approach methods (NAMs) in a regulatory context, criteria to define their readiness are necessary. The field of developmental neurotoxicity (DNT) testing is used to exemplify the application of readiness criteria. The costs and number of untested chemicals are overwhelming for in vivo DNT testing. Thus, there is a need for inexpensive, high-throughput NAMs, to obtain initial information on potential hazards, and to allow prioritization for further testing...
February 23, 2018: ALTEX
Weijia Gu, Yi Wang, Zhenmin Qiu, Jing Dong, Yuan Wang, Jie Chen
Microglia (MG) are the key cells involved in the innate immune response in the central nervous system, and their activation has been linked to inflammation and neurotoxicity by the production of proinflammatory cytokines. Recently, researchers have found that nonylphenol (NP), a ubiquitous endocrine disrupting chemical, could impair neurodevelopment and cognitive memory performance. However, whether NP affects the inflammatory responses of MG remains to be elucidated. The aim of this study was to explore the effects of NP on the inflammatory responses of BV2 MG and the underlying mechanisms...
February 27, 2018: Journal of Applied Toxicology: JAT
Anna Bal-Price, Francesca Pistollato, Magdalini Sachana, Stephanie K Bopp, Sharon Munn, Andrew Worth
Currently, the identification of chemicals that have the potential to induce developmental neurotoxicity (DNT) is based on animal testing. Since at the regulatory level, systematic testing of DNT is not a standard requirement within the EU or USA chemical legislation safety assessment, DNT testing is only performed in higher tiered testing triggered based on chemical structure activity relationships or evidence of neurotoxicity in systemic acute or repeated dose toxicity studies. However, these triggers are rarely used and, in addition, do not always serve as reliable indicators of DNT, as they are generally based on observations in adult rodents...
February 21, 2018: Toxicology and Applied Pharmacology
Karine Audouze, Olivier Taboureau, Philippe Grandjean
The need to prevent developmental brain disorders has led to an increased interest in efficient neurotoxicity testing. When an epidemic of microcephaly occurred in Brazil, Zika virus infection was soon identified as the likely culprit. However, the pathogenesis appeared to be complex, and a larvicide used to control mosquitoes responsible for transmission of the virus was soon suggested as an important causative factor. Yet, it is challenging to identify relevant and efficient tests that are also in line with ethical research defined by the 3Rs rule (Replacement, Reduction and Refinement)...
February 21, 2018: Toxicology and Applied Pharmacology
O G Zatsepina, O I Kechko, V A Mitkevich, S A Kozin, M M Yurinskaya, M G Vinokurov, M V Serebryakova, A P Rezvykh, M B Evgen'ev, A A Makarov
Neuronal dysfunction and loss associated with the accumulation of amyloid-β (Aβ) in the form of extracellular amyloid plaques and hyperphosphorylated tau in the form of intraneuronal neurofibrillary tangles represent key features of Alzheimer's disease (AD). Amyloid plaques found in the brains of AD patients are predominantly composed of Aβ42 and its multiple chemically or structurally modified isoforms. Recently, we demonstrated that Aβ42 with isomerised Asp7 (isoAβ42) which is one of the most abundant Aβ isoform in plaques, exhibited high neurotoxicity in human neuronal cells...
February 23, 2018: Scientific Reports
Andrea Terron, Susanne Hougaard Bennekou
There is a need for a more effective Developmental Neurotoxicity (DNT) screening which is scientifically driven by the fact that the developing nervous system might be more sensitive to exposures to some hazardous chemical. Additional concern comes from the recent societal concerns that toxic chemicals can contribute to the prevalence of neurodevelopment disabilities. Consequently, hazard identification and actions to reduce exposure to these chemicals is a priority in chemical risk assessment. To reach this goal a cost-efficient testing strategy based on a reliable in-vitro testing battery should be developed...
February 14, 2018: Toxicology and Applied Pharmacology
Ellen Fritsche, Philippe Grandjean, Kevin M Crofton, Michael Aschner, Alan Goldberg, Tuula Heinonen, Ellen V S Hessel, Helena Hogberg, Susanne Hougaard Bennekou, Pamela J Lein, Marcel Leist, William R Mundy, Martin Paparella, Aldert H Piersma, Magdalini Sachana, Gabriele Schmuck, Roland Solecki, Andrea Terron, Florianne Monnet-Tschudi, Martin F Wilks, Hilda Witters, Marie-Gabrielle Zurich, Anna Bal-Price
This consensus statement voices the agreement of scientific stakeholders from regulatory agencies, academia and industry that a new framework needs adopting for assessment of chemicals with the potential to disrupt brain development. An increased prevalence of neurodevelopmental disorders in children has been observed that cannot solely be explained by genetics and recently pre- and postnatal exposure to environmental chemicals has been suspected as a causal factor. There is only very limited information on neurodevelopmental toxicity, leaving thousands of chemicals, that are present in the environment, with high uncertainty concerning their developmental neurotoxicity (DNT) potential...
February 12, 2018: Toxicology and Applied Pharmacology
Eiki Kimura, Chiharu Tohyama
Mammalian attachment behaviors, such as crying, are essential for infant survival by receiving food, protection, and warmth from caregivers. Ultrasonic vocalization (USV) of infant rodents functions to promote maternal proximity. Impaired USV emission has been reported in mouse models of autism spectrum disorder, suggesting that USV is associated with higher brain function. In utero and lactational dioxin exposure is known to induce higher brain function abnormalities in adulthood; however, whether perinatal dioxin exposure affects behavior during infancy is unclear...
February 14, 2018: Archives of Toxicology
Jenifer A Bradley, Harry H Luithardt, Monica R Metea, Christopher J Strock
Drug induced seizure liabilities produce significant compound attrition during drug discovery. Currently available in vitro cytotoxicity assays cannot predict all toxicity mechanisms due to the failure of these assays to predict sublethal target specific electrophysiological liabilities. Identification of seizurogenic and other electrophysiological effects at early stages of the drug development process is important to ensure that safe candidate compounds can be developed while chemical design is taking place, long before these liabilities are discovered in costly preclinical in vivo studies...
February 8, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
Mizuho Hanaki, Kazuma Murakami, Sumie Katayama, Ken-Ichi Akagi, Kazuhiro Irie
(R)-Apomorphine (1) has the potential to reduce the accumulation of amyloid β-protein (Aβ42), a causative agent of Alzheimer's disease (AD). Although the inhibition of Aβ42 aggregation by 1 is ascribable to the antioxidative effect of its phenol moiety, its inhibitory mechanism at the molecular level remains to be fully elucidated. LC-MS and UV analyses revealed that 1 is autoxidized during incubation to produce an unstable o-quinone form (2), which formed a Michael adduct with Lys 16 and 28 of Aβ42. A further autoxidized form of 1 (3) with o-quinone and phenanthrene moieties suppressed Aβ42 aggregation comparable to 1, whereas treating 1 with a reductant, tris(2-carboxyethyl)phosphine diminished its inhibitory activity...
February 2, 2018: Bioorganic & Medicinal Chemistry
David Pamies, Katharina Block, Pierre Lau, Laura Gribaldo, Carlos Pardo, Paula Barreras, Lena Smirnova, Daphne Wiersma, Liang Zhao, Georgina Harris, Thomas Hartung, Helena T Hogberg
Growing concern suggests that some chemicals exert (developmental) neurotoxicity (DNT and NT) and are linked to the increase in incidence of autism, attention deficit and hyperactivity disorders. The high cost of routine tests for DNT and neurotoxicity (NT) assessment make it difficult to test the high numbers of existing chemicals. Thus, more cost effective neurodevelopmental models are needed. The use of induced pluripotent stem cells (iPSC) in combination with the emerging human 3D tissue culture platforms, present a novel tool to predicting and study human toxicity...
February 8, 2018: Toxicology and Applied Pharmacology
Ricardo Basto Souza, Annyta Fernandes Frota, Joana Silva, Celso Alves, Agnieszka Zofia Neugebauer, Susete Pinteus, José Ariévilo Gurgel Rodrigues, Edna Maria Silva Cordeiro, Raimundo Rafael de Almeida, Rui Pedrosa, Norma Maria Barros Benevides
This study assessed the antioxidant, antimicrobial, cytotoxic, anticancer and neuroprotective activities of the kappa(k)-carrageenan isolated from the red alga Hypnea musciformis (Hm-SP). As expected, the chemical spectrum of the k-carrageenan from Hm-SP was confirmed by Fourier transform infrared (FT-IR) spectroscopy. Hm-SP revealed an antibacterial and antifungal action against Staphylococcus aureus and Candida albicans, respectively. Hm-SP did not promoted cytotoxic effects against Human breast cancer (MCF-7) and Human neuroblastoma (SH-SY5Y)...
February 7, 2018: International Journal of Biological Macromolecules
Johannes Delp, Simon Gutbier, Stefanie Klima, Lisa Hoelting, Kevin Pinto-Gil, Jui-Hua Hsieh, Michael Aichem, Karsten Klein, Falk Schreiber, Raymond R Tice, Manuel Pastor, Mamta Behl, Marcel Leist
The (developmental) neurotoxicity hazard is still unknown for most chemicals. Establishing a test battery covering most of the relevant adverse outcome pathways may close this gap, without requiring a huge animal experimentation program. Ideally, each of the assays would cover multiple mechanisms of toxicity. One candidate test is the human LUHMES cell-based NeuriTox test. To evaluate its readiness for larger-scale testing, a proof of concept library assembled by the U.S. National Toxicology Program (NTP) was screened...
January 21, 2018: ALTEX
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