Cellular Mechanisms for Developmental Toxicity of Chlorpyrifos: Targeting the Adenylyl Cyclase Signaling Cascade

Song, Xun; Seidler, Frederic J.; Saleh, J. L.; Zhang, J.; Padilla, Stephanie; Slotkin, Theodore A.

doi:10.1006/taap.1997.8171

Cited by 241 publications

(215 citation statements)

References 48 publications

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“…For both agents, we utilized doses below the threshold for growth retardation and systemic toxicity [16,91,109]: 1 mg/kg for CPF and 1 or 2 mg/kg for DZN. This CPF treatment and the higher dose of DZN produce neurotoxicity in developing rat brain while eliciting less than 20% cholinesterase inhibition, well below the 70% threshold necessary for symptoms of cholinergic hyperstimulation [20], whereas the lower dose of DZN produces no measurable inhibition in male neonates [86,87,97,100,109]. These treatments thus resemble the nonsymptomatic exposures reported in pregnant women [32] and are within the range of expected fetal and childhood exposures after routine home application or in agricultural communities [43,70].…”

Section: Animal Treatmentsmentioning

confidence: 87%

“…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%

“…We then compared the results for CPF with those for DZN, for which far less is known, in order to emphasize points of similarity and difference that may enable the prediction of disparities in the ultimate neurodevelopmental outcomes of these two organophosphates. We concentrated on doses that evoke no cholinesterase inhibition or barely-detectable inhibition, too low to elicit any signs of cholinergic hyperstimulation [97,100]. For our evaluations of gene transcription, we chose specific pathways involved in: (a) neural cell growth and neurite formation; (b) transcription factors and cell signaling cascades that mediate neural cell differentiation; (c) cytotoxic events including oxidative stress, apoptosis and expression of ionotropic glutamate receptors (iGluRs); and (d) neurotransmitter pathways known to be especially targeted by CPF.…”

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

191

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: Animal Treatmentsmentioning

confidence: 87%

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

confidence: 99%

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

191

208

View full text Add to dashboard Cite

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“…Adenylate cyclase activity was determined using the protocol described in earlier studies (Liu et al, 2005;Song et al, 1997). Briefly, cells were plated in 100 × 20 mm Petri dishes.…”

Section: Western Blotting Analysismentioning

confidence: 99%

Effects of fluorotelomer alcohol 8:2 FTOH on steroidogenesis in H295R cells: Targeting the cAMP signalling cascade

Liu

Zhang

Chang

et al. 2010

Toxicology and Applied Pharmacology

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“…Effects were most prominent in adulthood, with exposure of the three earlier stages the most effective. Interestingly, the effects on cell signalling pathways did not appear to be related to the inhibition of acetylcholinesterase, the pesticidal mode of action of chlorpyrifos (Song et al, 1997).…”

Section: Consequences Of Exposuresmentioning

confidence: 94%

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

Liu

Xia

Guo

et al. 2012

J Expo Sci Environ Epidemiol

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The urinary metabolites of phthalates are well-accepted exposure biomarkers for adults and children older than 6 years but are not commonly used for infants owing to non-convenient sampling. In the light of this situation, a novel sampling method based on monitoring the urine expressed from the gel diaper was developed. The urine was expressed from the gel absorbent after mixing the absorbent with CaCl2 and then collected by a laboratory-made device; the urinary phthalate metabolites were extracted and cleaned using a solid-phase extraction (SPE) column and analyzed with high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry / mass spectrometry. To evaluate the method's feasibility, the following factors were investigated: the proportion of CaCl2 to gel absorbent, the urination volume variation and the target compounds' deposition bias in the diaper, the matrix blank of the different diaper brands, the storage stabilities and the recoveries of creatinine and phthalate metabolites in the expressed urine. Mono-methyl phthalate, mono-ethyl phthalate, mono-butyl phthalate, mono-benzyl phthalate, mono-2-ethylhexyl phthalate and mono-2-ethyl-5-oxohexyl phthalate were involved. 70-80% of the urine can be expressed from the diaper, and the expressed spiking recoveries and the limit of detection of mono-phthalates ranged from 88.5-115% and 0.21-0.50 ng/ml. The method was applied to measure phthalate metabolites in 65 gel diaper samples from 15 infants, and the pilot data suggests the infants are commonly exposed to phthalates. In summary, the method for monitoring of infant exposure to phthalates is sound and validated, and the potential health effects from the vulnerable infants' exposure to phthalates should be concerned.39th Scientific Research Foundation for the Returned Overseas Chinese Scholars (SRF for ROCS); Hundred Talent Program of Chinese Academy of Sciences (CAS); CAS/SAFEA International Partnership Program for Creative Research Teams [KZCX2-YW-T08

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Cellular Mechanisms for Developmental Toxicity of Chlorpyrifos: Targeting the Adenylyl Cyclase Signaling Cascade

Cited by 241 publications

References 48 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

Effects of fluorotelomer alcohol 8:2 FTOH on steroidogenesis in H295R cells: Targeting the cAMP signalling cascade

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

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