Developmental neurotoxicity of chlorpyrifos in vivo and in vitro: effects on nuclear transcription factors involved in cell replication and differentiation

Crumpton, T.L.; Seidler, Frederic J.; Slotkin, T A

doi:10.1016/s0006-8993(99)02357-4

Cited by 152 publications

(113 citation statements)

References 54 publications

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“…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%

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: Cpf and Dzn Effects On Transcription Control And Cell Signalingmentioning

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

191

208

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“…Although, CPF has been shown to be relatively safe in adult animals, newly discovered evidence indicates that CPF is a developmental neurotoxicant in the fetus and is thus harmful (Garcia et al 2003). In animals and cellular models, chlorpyrifos inhibits neural cellular replication (Qian et al 2001), interferes with cellular differentiation (Crumpton et al 2000), evokes oxidative stress, alters neurotransmission (Dam et al 1999;Bloomquist et al 2002;Karanth et al 2006;Slotkin and Seidler, 2007) and induces neurobehavioral changes (Ricceri et al 2006). Additionally, animals exposed to CPF in utero or as juveniles display motor and cognitive delays (Moser 2000).…”

Section: Introductionmentioning

confidence: 99%

Characterization of chlorpyrifos-induced apoptosis in placental cells

Saulsbury¹,

Heyliger²,

Wang³

et al. 2008

Toxicology

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The mechanism by which chlorpyrifos exerts its toxicity in fetal and perinatal animals has yet to be elucidated. Since the placenta is responsible for transport of nutrients and is a major supplier hormones to the fetus, exposure to xenobiotics that alter the function or viability of placenta cells could ostensibly alter the development of the fetus. In this study, JAR cells were used to determine if CPF and the metabolites 3,5,6-trichloro-2-pyridinol (TCP) and chlorpyrifos-oxon (CPO) are toxic to the placenta. Our results indicate that chlorpyrifos (CPF), and its metabolite chlorpyrifos-oxon (CPO) caused a dose-dependent reduction in cellular viability with CPF being more toxic than its metabolites. Chlorpyrifos-induced toxicity was characterized by the loss of mitochondrial potential, the appearance of nuclear condensation and fragmentation, down-regulation of Bcl-2 as well as upregulation of TNFα and FAS mRNA. Pharmacological inhibition of FAS, nicotinic and TNF-α receptors did not attenuate CPF-induced toxicity. Atropine exhibited minimal ability to reverse toxicity. Furthermore, signal transduction inhibitors PD98059, SP600125, LY294002 and U0126 failed to attenuate toxicity; however, SB202190 (inhibitor of p38α and p38β MAPK) sensitized cells to CPF-induced toxicity. Pan-caspase inhibitor Q-VD-OPh produced a slight but significant reversal of CPF-induced toxicity indicating that the major caspase pathways are not integral to CPF-induced toxicity. Taken collectively, these results suggest that chlorpyrifos induces apoptosis in placental cells through pathways not dependent on FAS/TNF signaling, activation of caspases or inhibition of cholinesterase. In addition, our data further indicates that activation of p38 MAPK is integral to the protection cells against CPF-induced injury.

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“…The cyclic AMP (cAMP) signaling pathway has received particular attention because this second messenger coordinates the critical transition from cell replication to cell differentiation in virtually all prokaryotic and eukaryotic cells (Bhat et al 1983;Claycomb 1976;Guidotti 1972;Hultgårdh-Nilsson et al 1994;Van Wijk et al 1973). A number of studies in the developing brain have centered on the effects of CPF on the receptors and signaling proteins that control the activity of adenylyl cyclase (AC), the enzyme that synthesizes cAMP, as well as on the downstream elements that are targets for cAMP (Crumpton et al 2000;Garcia et al 2001;Meyer et al 2003;Olivier et al 2001;Schuh et al 2002;Song et al 1997;Zhang et al 2002).…”

mentioning

confidence: 99%

Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling.

Meyer

Seidler

Slotkin

2004

Environ Health Perspect

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The fetal and neonatal neurotoxicity of chlorpyrifos (CPF) and related insecticides is a major concern. Developmental effects of CPF involve mechanisms over and above cholinesterase inhibition, notably events in cell signaling that are shared by nonneural targets. In the present study, we evaluated the immediate and long-term effects of CPF exposure of rats during different developmental windows [gestational days (GD) 9-12 or 17-20, postnatal days (PN) 1-4 or 11-14] on the adenylyl cyclase (AC) signaling cascade in the heart and liver. In addition to basal AC activity, we assessed the responses to direct AC stimulants (forskolin, Mn 2+ ); to isoproterenol and glucagon, which activate signaling through specific membrane receptors; and to sodium fluoride, which activates the G-proteins that couple the receptors to AC. Few immediate effects on AC were apparent when CPF doses remained below the threshold for systemic toxicity. Nevertheless, CPF exposures on GD9-12, GD17-20, or PN1-4 elicited sex-selective effects that emerged by adulthood (PN60), whereas later exposure (PN11-14) elicited smaller, nonsignificant effects, indicative of closure of the window of vulnerability. Most of the effects were heterologous, involving signaling elements downstream from the receptors, and thus were shared by multiple inputs; superimposed on this basic pattern, there were also selective alterations in receptor-mediated responses. These results suggest that the developmental toxicity of CPF extends beyond the nervous system, to include cell signaling cascades that are vital to cardiac and hepatic homeostasis. Future work needs to address the potential implications of these effects for cardiovascular and metabolic disorders that may emerge long after the end of CPF exposure.

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Developmental neurotoxicity of chlorpyrifos in vivo and in vitro: effects on nuclear transcription factors involved in cell replication and differentiation

Cited by 152 publications

References 54 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

Characterization of chlorpyrifos-induced apoptosis in placental cells

Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling.

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