Organophosphate Toxicology:  Safety Aspects of Nonacetylcholinesterase Secondary Targets

Casida, John E.; Quistad, Gary B.

doi:10.1021/tx0499259

Cited by 473 publications

(345 citation statements)

References 191 publications

(264 reference statements)

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“…Our results also indicate that AC itself is a major target for the effects of organophosphates unrelated to anticholinesterase actions [17,86,87,89,112]. Both CPF and DZN altered the expression of genes encoding multiple subtypes of AC as well as those for modulators of AC activity.…”

Section: Cpf and Dzn Effects On Transcription Control And Cell Signalingsupporting

confidence: 51%

“…One notable distinction was seen for grk1, which encodes the receptor kinase that uncouples G-proteins from their ability to signal through α-subunits: DZN had a much greater effect than CPF, suggesting a greater potential impact on receptor coupling capabilities and therefore on the efficiency of receptor signaling in general. As deficiencies in GPCR function have already been clearly established for CPF [17,64,106,114], we expect that this might be an even greater problem with DZN exposure. The specificity of these actions was demonstrated further by the relative sparsity of effects on the genes encoding the β and γ subunits of the heterotrimeric G-proteins, which showed only sporadic differences of generally smaller magnitude.…”

Section: Cpf and Dzn Effects On Transcription Control And Cell Signalingmentioning

confidence: 90%

“…The adverse effects of CPF on brain development prominently feature mechanisms centered around cell signaling cascades that control the expression and function of nuclear transcription factors required for neural cell differentiation [17,22,36,47,64,65,83,100,106]. Among the best studied is the pathway connecting GPCRs to the generation of cAMP and the downstream effectors controlled by cAMP, such as PKA and the transcription factors AP-1, Sp1 and CREB.…”

Section: Cpf and Dzn Effects On Transcription Control And Cell Signalingmentioning

confidence: 99%

“…Despite their widespread use [17], organophosphate insecticides are a major concern for human health because of their propensity to damage the developing brain at exposures below the threshold for signs of systemic intoxication [55,56,62,72,73,86,87,108]. Although it was originally thought that these agents act solely through inhibition of cholinesterase and consequent cholinergic hyperstimulation, it is now evident that there are multiple mechanisms that contribute to neurodevelopmental abnormalities [10,17,42,73,74,77,112].…”

Section: Introductionmentioning

confidence: 99%

“…Although it was originally thought that these agents act solely through inhibition of cholinesterase and consequent cholinergic hyperstimulation, it is now evident that there are multiple mechanisms that contribute to neurodevelopmental abnormalities [10,17,42,73,74,77,112]. Accordingly, whereas all the organophosphates share cholinesterase as a target, they are likely to differ to a greater or lesser extent in their effects unrelated to that particular mechanism.…”

Section: Introductionmentioning

confidence: 99%

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Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

Slotkin

Seidler

2007

Brain Research Bulletin

193

208

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Organophosphates affect mammalian brain development through a variety of mechanisms beyond their shared property of cholinesterase inhibition. We used microarrays to characterize similarities and differences in transcriptional responses to chlorpyrifos and diazinon, assessing defined gene groupings for the pathways known to be associated with the mechanisms and/or outcomes of chlorpyrifos-induced developmental neurotoxicity. We exposed neonatal rats to daily doses of chlorpyrifos (1 mg/kg) or diazinon (1 or 2 mg/kg) on postnatal days 1-4 and evaluated gene expression profiles in brainstem and forebrain on day 5; these doses produce little or no cholinesterase inhibition. We evaluated pathways for general neural cell development, cell signaling, cytotoxicity and neurotransmitter systems, and identified significant differences for >60% of 252 genes. Chlorpyrifos elicited major transcriptional changes in genes involved in neural cell growth, development of glia and myelin, transcriptional factors involved in neural cell differentiation, cAMP-related cell signaling, apoptosis, oxidative stress, excitotoxicity, and development of neurotransmitter synthesis, storage and receptors for acetylcholine, serotonin, norepinephrine and dopamine. Diazinon had similar effects on many of the same processes but also showed major differences from chlorpyrifos. Our results buttress the idea that different organophosphates target multiple pathways involved in neural cell development but also that they deviate in key aspects that may contribute to disparate neurodevelopmental outcomes. Equally important, these pathways are compromised at exposures that are unrelated to biologically significant cholinesterase inhibition and its associated signs of systemic toxicity. The approach used here demonstrates how planned comparisons with microarrays can be used to screen for developmental neurotoxicity.

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Section: Cpf and Dzn Effects On Transcription Control And Cell Signalingsupporting

confidence: 51%

Section: Cpf and Dzn Effects On Transcription Control And Cell Signalingmentioning

confidence: 90%

Section: Cpf and Dzn Effects On Transcription Control And Cell Signalingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

Slotkin

Seidler

2007

Brain Research Bulletin

193

208

View full text Add to dashboard Cite

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Organophosphorus Pesticides

2023

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Organophosphates (OP) inhibit serine hydrolases by phosphorylating serine residue. Exposure to OPs always involves acetylcholine esterase (AChE) inhibition, which is responsible for the degradation of acetylcholine (ACh), controlling the levels of ACh at the nerve endings. Inactivation/inhibition of AChE causes excessive accumulation of ACh at the neuromuscular junctions and synapses activating both sympathetic and parasympathetic processes causing both muscarinic and nicotinic toxicity. The muscarinic symptoms include salivation, diaphoresis, abdominal cramps, diarrhea, vomiting, miosis, bronchorrhea, bradycardia, coma, and seizure. Nicotinic symptoms are fasciculations, flaccid paralysis, and tachycardia. The most common cause of death is respiratory failure with refractory hypotension. Recovery from OP toxicity is linked to the restoration of OP‐inhibited AChE, which can be revived by oximes or regeneration of the enzyme, certain OPs bind irreversibly with AChE render it permanently inactive. The secondary OP targets in humans are butyrylcholinesterase (BChE), a sink for OP, and neuropathy target esterase, inhibition of which causes delayed neuropathy. The OPs are not only used for the management of pests in agriculture but also used in the treatment of human diseases, such as glaucoma with echothiophate to increase drainage of intraocular fluid reducing ocular pressure, schistosomiasis, and Alzheimer's with metrifonate. Metrifonate inhibits AChE in schistosomes, which is abundant in the muscles of the parasite. Metrifonate enhances central nervous system (CNS) cholinergic neurotransmission improving cognitive function in Alzheimer's patients. This chapter describes the AChE inhibition and toxicity of each OP and regeneration of AChE by oximes along with regulations based on the available data for individual OPs.

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Toxicology of Organophosphate Nerve Agents

Marrs

2007

Chemical Warfare Agents

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Organophosphate Toxicology: Safety Aspects of Nonacetylcholinesterase Secondary Targets

Cited by 473 publications

References 191 publications

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

Organophosphorus Pesticides

Toxicology of Organophosphate Nerve Agents

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