Sarin (nerve agent GB)-induced differential expression of mRNA coding for the acetylcholinesterase gene in the rat central nervous system

Damodaran, Tirupapuliyur V.; Jones, Katherine H.; Patel, Anand G.; Abou‐Donia, Mohamed B.

doi:10.1016/s0006-2952(03)00160-6

Cited by 45 publications

(21 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First and foremost, we did not observe any signs of upregulation of cholinesterase-related genes, as would be expected from biologically significant degrees of cholinesterase inhibition consequent to the actions of chlorpyrifos oxon or diazoxon, the active metabolites that are primarily responsible for anticholinesterase effects. In contrast to our results in neonatal rats given low doses of CPF or DZN, ache is highly induced when sarin is given to adult rats in doses above the threshold for lethality [29]. Given the small degree of cholinesterase inhibition by the treatments used here [97,100], there is likely to be a rapid synthesis of new enzyme molecules that offsets any inhibition simply because of the high rate of growth in the neonate and consequent rapid rise in new cholinesterase molecules [57]; under those circumstances, transcriptional activation is probably not necessary to maintain the normal level of enzyme protein.…”

Section: Cpf and Dzn Effects On Neurotransmitter Systemscontrasting

confidence: 99%

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

190

208

View full text Add to dashboard Cite

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.

show abstract

Section: Cpf and Dzn Effects On Neurotransmitter Systemscontrasting

confidence: 99%

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

190

208

View full text Add to dashboard Cite

show abstract

“…Hence, we studied the effect of a single 0.5 LD 50 subcutaneous dose along with chronic 15 μg kg −1 (30 days) subcutaneous sarin administration on differential regulation of acetylcholinesterase gene expression. Earlier Damodaran et al (2003) reported that a single intramuscular injection of 0.5 LD 50 sarin caused an immediate elevation in transcription of AChE mRNA in different brain regions at 1 h and persisted up to 2 h. This elevated transcription came back to control levels by one day after exposure. The cerebellum showed maximum induction.…”

Section: Discussionmentioning

confidence: 84%

“…However, on subcutaneous administration of sarin, our results showed steady down regulation in mRNA expression. Damodaran et al (2003) inferred that promoter activation of key cholinergic genes may be involved in the activation of AChE mRNA expression. It has been proposed that sarin-induced toxicity leads to cholinergic dysfunction through multiple mechanisms (Khan et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Differential mRNA expression of acetylcholinesterase in the central nervous system of rats with acute and chronic exposure of sarin & physostigmine

Bansal

Waghmare

Anand

et al. 2009

J of Applied Toxicology

View full text Add to dashboard Cite

A time-course study was carried out to measure the acetylcholinesterase (AChE) gene expression in the brain of female rats exposed to different doses of sarin and physostigmine. Short-term effects were studied with an acute single subcutaneous dose (s.c.) of 80 microg kg(-1) (0.5 x LD(50)) sarin. Cortex and cerebellum showed a significant decline in AChE mRNA expression at 2.5, 24 and 72 h. Biochemical studies showed that plasma butrylcholinesterase (BChE) and brain AChE activities were significantly decreased at 2.5 h, which came back to near control values by 24 h in both cases. For long-term chronic studies, three groups of female rats received daily doses of physostigmine (0.1 mg kg(-1) day(-1)) intramuscularly (i.m.), sarin (15 microg kg(-1) day(-1)) s.c. independently and a combined dose of physostigmine (i.m.) (0.1 mg kg(-1) day(-1)) followed by sarin (s.c.) (15 microg kg(-1) day(-1)) continuously for 30 days. Differential AChE mRNA levels in cortex and cerebellum of rat brain were observed after 30 days and after a lag period of another 30 days with no further administration. Plasma (BChE) and brain (AChE) showed irregular inhibition profile in biochemical studies at 30 days and returned to control levels after 60 days. The acute single subcutaneous administration of sarin for short-term as well as chronic long-term studies showed that AChE inhibition alone does not lead to observed changes in mRNA expression of AChE gene. These observations further suggest that route of administration as well as dose exposure regimen also contributes to the regulation of AChE mRNA expression.

show abstract

“…Early work by Damodaran et al suggested differential distribution of acetylcholinesterase (Damodaran et al, 2003) and alpha tubulin (Damodaran et al, 2002) mRNA expression levels in different regions of the rat brain following exposure to the nerve agent sarin (GB). While these targeted mRNA studies were restricted to only a limited set of genes, they paved the way for additional largescale genomics analyses of GB-induced toxicity.…”

Section: Genomics Applications To Cwasmentioning

confidence: 99%

Genomics and proteomics in chemical warfare agent research: Recent studies and future applications

Everley¹,

Dillman²

2010

Toxicology Letters

View full text Add to dashboard Cite

a b s t r a c tMedical research on the effects of chemical warfare agents (CWAs) has been ongoing for nearly 100 years, yet these agents continue to pose a serious threat to deployed military forces and civilian populations. CWAs are extremely toxic, relatively inexpensive, and easy to produce, making them a legitimate weapon of choice for terrorist organizations. While the mechanisms of action for many CWAs have been known for years, questions about their molecular effects following acute and chronic exposure remain largely unanswered. Global approaches that can pinpoint which cellular pathways are altered in response to CWAs and characterize long-term toxicity have not been widely used. Fortunately, innovations in genomics and proteomics technologies now allow for thousands of genes and proteins to be identified and subsequently quantified in a single experiment. Advanced bioinformatics software can also help decipher large-scale changes observed, leading to mapping of signaling pathways, functional characterization, and identification of potential therapeutic targets. Here we present an overview of how genomics and proteomics technologies have been applied to CWA research and also provide a series of questions focused on how these techniques could further our understanding of CWA toxicity.

show abstract

Sarin (nerve agent GB)-induced differential expression of mRNA coding for the acetylcholinesterase gene in the rat central nervous system

Cited by 45 publications

References 35 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

Differential mRNA expression of acetylcholinesterase in the central nervous system of rats with acute and chronic exposure of sarin & physostigmine

Genomics and proteomics in chemical warfare agent research: Recent studies and future applications

Contact Info

Product

Resources

About