Chlorpyrifos and its metabolites alter gene expression at non-cytotoxic concentrations in D3 mouse embryonic stem cells under in vitro differentiation: Considerations for embryotoxic risk assessment

Estevan, Carmen; Vilanova, Eugenio; Sogorb, Miguel A.

doi:10.1016/j.toxlet.2012.11.026

Cited by 34 publications

(36 citation statements)

References 28 publications

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“…The near equivalence of all three organophosphate pesticides seen here also holds true for the second decision node (neurotransmitter phenotype) seen in PC12 cells (Slotkin et al, 2007). In embryonic stem cell models that are not yet committed to a neural phenotype, chlorpyrifos and metabolites impair expression of genes involved in general differentiation (Estevan et al, 2013, 2014) as well as subsequent differentiation into neurons (Visan et al 2012). This does not match what we saw here for organophosphate effects on embryonic NSCs, since we did not find general inhibition of differentiation, but rather saw only a selective suppression of the glial phenotype.…”

Section: Discussionmentioning

confidence: 99%

Diverse neurotoxicants target the differentiation of embryonic neural stem cells into neuronal and glial phenotypes

et al. 2016

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The large number of compounds that need to be tested for developmental neurotoxicity drives the need to establish in vitro models to evaluate specific neurotoxic endpoints. We used neural stem cells derived from rat neuroepithelium on embryonic day 14 to evaluate the impact of diverse toxicants on their ability to differentiate into glia and neurons: a glucocorticoid (dexamethasone), organophosphate insecticides (chlorpyrifos, diazinon, parathion), insecticides targeting the GABAA receptor (dieldrin, fipronil), heavy metals (Ni2+, Ag+), nicotine and tobacco smoke extract. We found three broad groupings of effects. One diverse set of compounds, dexamethasone, the organophosphate pesticides, Ni2+ and nicotine, suppressed expression of the glial phenotype while having little or no effect on the neuronal phenotype. The second pattern was restricted to the pesticides acting on GABAA receptors. These compounds promoted the glial phenotype and suppressed the neuronal phenotype. Notably, the actions of compounds eliciting either of these differentiation patterns were clearly unrelated to deficits in cell numbers: dexamethasone, dieldrin and fipronil all reduced cell numbers, whereas organophosphates and Ni2+ had no effect. The third pattern, shared by Ag+ and tobacco smoke extract, clearly delineated cytotoxicity, characterized major cell loss with suppression of differentiation into both glial and neuronal phenotypes; but here again, there was some selectivity in that glia were suppressed more than neurons. Our results, from this survey with diverse compounds, point to convergence of neurotoxicant effects on a specific “decision node” that controls the emergence of neurons and glia from neural stem cells.

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Section: Discussionmentioning

confidence: 99%

Diverse neurotoxicants target the differentiation of embryonic neural stem cells into neuronal and glial phenotypes

et al. 2016

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“…Moreover, TCP has higher water solubility as compared with the parent compound; hence, it leaches to the water bodies causing widespread contamination of aquatic environments (Vogel et al 2008;Xu et al 2008;Grzelak et al 2012;Watts 2012). CP and TCP toxicity has been linked to broad-spectrum effects including neurological disorders, developmental disorders, autoimmune disorders and interruption of many vital functions in higher animals and humans (Sogorb et al 2004;Mehta et al 2008;Alavanja & Bonner 2012;Ventura et al 2012;Estevan et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Biodegradation of chlorpyrifos and 3, 5, 6‐trichloro‐2‐pyridinol by a novel rhizobial strain Mesorhizobium sp. HN3

Jabeen

Iqbal

Anwar

2014

Water & Environment J

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A chlorpyrifos (CP) and 3,5,6‐trichloro‐2‐pyridinol (TCP) degrading bacterial strain, Mesorhizobium sp. HN3, was isolated and characterized. Mesorhizobium sp. HN3 degraded CP efficiently up to 400 mg/L initial concentration at wide range of temperatures (30–40°C) and pH (6.0–8.0). However, optimal degradation of CP was achieved at 37°C and neutral pH (7.0) at an initial inoculum density 2 × 107 colony forming unit/mL of culture medium. Kinetic parameters for CP degradation by Mesorhizobium sp. HN3 were estimated at different initial concentrations. Cultures exhibited significant variation (P ≤ 0.05) in the specific growth rate (μ), cell mass formation rate (QX) and the substrate uptake rate (QS) during degradation of CP. The values of kinetic parameters increased up to 100 mg/L CP and decreased at higher concentration. Investigation of degradation metabolites indicated that CP is converted to diethylthiophosphate and TCP that leads to the formation of 3,5,6‐trichloro‐2‐methoxypyridine.

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“…Thus, by selecting CPO for the model development, the specific effects of the parental compound as well as the effect of bioactivation were not considered. CPO is also a well-known developmental neurotoxicant (Estevan et al 2013, 2014; Sogorb et al 2016), and subacute exposure of zebrafish embryos to this compound inhibits the axonal growth of sensory neurons, primary motor neurons and secondary motor neurons (Jacobson et al 2010; Yang et al 2011). Although most structures of the nervous system of the zebrafish larvae are well developed at 7 days post-fertilization and the adverse effects found at different levels of organization are similar to those reported in adult mammals with severe acute OP intoxication, the possibility of adverse effects on the development of specific structures of the nervous system in the exposed larvae cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication

et al. 2016

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Acute organophosphorus (OP) intoxication is a worldwide clinical and public health problem. In addition to cholinergic crisis, neurodegeneration and brain damage are hallmarks of the severe form of this toxidrome. Recently, we generated a chemical model of severe acute OP intoxication in zebrafish that is characterized by altered head morphology and brain degeneration. The pathophysiological pathways resulting in brain toxicity in this model are similar to those described in humans. The aim of this study was to assess the predictive power of this zebrafish model by testing the effect of a panel of drugs that provide protection in mammalian models. The selected drugs included “standard therapy” drugs (atropine and pralidoxime), reversible acetylcholinesterase inhibitors (huperzine A, galantamine, physostigmine and pyridostigmine), N-methyl-d-aspartate (NMDA) receptor antagonists (MK-801 and memantine), dual-function NMDA receptor and acetylcholine receptor antagonists (caramiphen and benactyzine) and anti-inflammatory drugs (dexamethasone and ibuprofen). The effects of these drugs on zebrafish survival and the prevalence of abnormal head morphology in the larvae exposed to 4 µM chlorpyrifos oxon [1 × median lethal concentration (LC50)] were determined. Moreover, the neuroprotective effects of pralidoxime, memantine, caramiphen and dexamethasone at the gross morphological level were confirmed by histopathological and transcriptional analyses. Our results demonstrated that the zebrafish model for severe acute OP intoxication has a high predictive value and can be used to identify new compounds that provide neuroprotection against severe acute OP intoxication.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1851-3) contains supplementary material, which is available to authorized users.

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Chlorpyrifos and its metabolites alter gene expression at non-cytotoxic concentrations in D3 mouse embryonic stem cells under in vitro differentiation: Considerations for embryotoxic risk assessment

Cited by 34 publications

References 28 publications

Diverse neurotoxicants target the differentiation of embryonic neural stem cells into neuronal and glial phenotypes

Diverse neurotoxicants target the differentiation of embryonic neural stem cells into neuronal and glial phenotypes

Biodegradation of chlorpyrifos and 3, 5, 6‐trichloro‐2‐pyridinol by a novel rhizobial strain Mesorhizobium sp. HN3

Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication

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