Is oxidative stress involved in the developmental neurotoxicity of chlorpyrifos?

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

doi:10.1016/s0165-3806(00)00045-6

Cited by 119 publications

(117 citation statements)

References 39 publications

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“…The antimitotic effects of CPF Campbell et al 1997;Dam et al 1998;Garcia et al 2001;Qiao et al 2001;Song et al 1998;Whitney et al 1995) could target the fetal liver because of its extremely rapid rate of cell acquisition and because this tissue achieves high levels of CPF and its metabolites (Hunter et al 1999). Additionally, the oxidative stress caused by CPF is likely to evoke hepatic cell damage and loss (Crumpton et al 2000;Garcia et al 2001;Jett and Navoa 2000), so sensitivity could depend on the relative state of development of enzymes generating reactive oxygen species, compared with those required for the deactivation of free radicals and/or catabolism of CPF (Padilla et al 2000). In any case, the effects on the fetal liver stand in direct contrast to the pattern seen for exposure in the neonatal period: postnatal CPF, which has a profound effect on brain cell development Pope 1999;Rice and Barone 2000;Slotkin 1999), does not evoke substantial deficits in liver weight (Auman et al 2000); however, it does alter cell signaling cascades linked to neurotransmitter receptors (Auman et al 2000), reinforcing the concept that, as in the developing brain, disruption of CPF-induced cellto-cell communication is separable from generalized toxicity or growth impairment.…”

Section: Discussionmentioning

confidence: 99%

Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period?

Qiao

Seidler

Padilla

et al. 2002

Environ Health Perspect

119

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Previously, we found that exposure of neonatal rats to chlorpyrifos (CPF) produced brain cell damage and loss, with resultant abnormalities of synaptic development. We used the same biomarkers to examine prenatal CPF treatment so as to define the critical period of vulnerability. One group of pregnant rats received CPF (subcutaneous injections in dimethyl sulfoxide vehicle) on gestational days (GD) 17-20, a peak period of neurogenesis; a second group was treated on GD9-12, the period of neural tube formation. In the GD17-20 group, the threshold for a reduction in maternal weight gain was 5 mg/kg/day; at or below that dose, there was no evidence (GD21) of general fetotoxicity as assessed by the number of fetuses or fetal body and tissue weights. Above the threshold, there was brain sparing (reduced body weight with an increase in brain/body weight ratio) and a targeting of the liver (reduced liver/body weight). Indices of cell packing density (DNA per gram of tissue) and cell number (DNA content) similarly showed effects only on the liver; however, there were significant changes in the protein/DNA ratio, an index of cell size, in fetal brain regions at doses as low as 1 mg/kg, below the threshold for inhibition of fetal brain cholinesterase (2 mg/kg). Indices of cholinergic synaptic development showed significant CPF-induced defects but only at doses above the threshold for cholinesterase inhibition. With earlier CPF treatment (GD9-12), there was no evidence of general fetotoxicity or alterations of brain cell development at doses up to the threshold for maternal toxicity (5 mg/kg), assessed on GD17 and GD21; however, augmentation of cholinergic synaptic markers was detected at doses as low as 1 mg/kg. Compared with previous work on postnatal CPF exposure, the effects seen here required doses closer to the threshold for fetal weight loss; this implies a lower vulnerability in the fetal compared with the neonatal brain. Although delayed neurotoxic effects of prenatal CPF may emerge subsequently in development, our results are consistent with the preferential targeting of late developmental events such as gliogenesis, axonogenesis, and synaptogenesis.

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Section: Discussionmentioning

confidence: 99%

Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period?

Qiao

Seidler

Padilla

et al. 2002

Environ Health Perspect

119

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“…In addition, Slotkin et al (2005) have shown that CPF can evoke lipid peroxidation in the developing rat brain at concentrations that only cause mild signs of systemic toxicity. Moreover, Crumpton et al (2000) observed a concentration-dependent increase in reactive oxygen species formation in response to CPF exposure in PC12 cells (commonly used as a neuronal model). We did not detect significant increases in the production of superoxide in this study (at the concentrations of CPF and CPO we evaluated); however, we cannot completely rule out the possibility that low levels of superoxide (i.e., below our limits of detection) could be produced over time in neurons exposed to OPs potentially leading to alterations of mitochondrial dynamics.…”

Section: Chlorpyrifos Alters Mitochondrial Dynamics 347mentioning

confidence: 98%

Effects of Chlorpyrifos and Chlorpyrifos-Oxon on the Dynamics and Movement of Mitochondria in Rat Cortical Neurons

Middlemore-Risher¹,

Adam²,

Lambert³

et al. 2011

J Pharmacol Exp Ther

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Organophosphate (OP)-based pesticides have been used extensively for decades, and as a result, they have become almost ubiquitous in our environment. There is clinical and animal evidence to suggest that chronic exposures to OPs can lead to cognitive dysfunction and other neurological abnormalities, although the mechanism for these effects is unknown. We previously reported that repeated, subthreshold exposures (defined as doses not associated with signs of acute toxicity) to the commonly used OP chlorpyrifos (CPF) resulted in protracted impairments in the performance of attention and memory-related tasks in rodents as well as deficits in axonal transport ex vivo (in the sciatic nerve). Here, we investigated the effects of CPF and its active metabolite CPF oxon (CPO) on the dynamics and movement of mitochondria in rat primary cortical neurons using time-lapse imaging techniques. Exposure to CPF (1.0 -20.0 M) or CPO (5.0 nM-20.0 M) for 1 or 24 h resulted in a concentration-dependent increase in mitochondrial length, a decrease in mitochondrial number (indicative of increased fusion events), and a decrease in their movement in axons. The changes occurred at concentrations of CPF and CPO that did not inhibit acetylcholinesterase activity (the commonly cited mechanism of acute OP toxicity), and they were not blocked by cholinergic receptor antagonists. Furthermore, the changes did not seem to be associated with direct (OP-related) effects on mitochondrial viability or function (i.e., mitochondrial membrane potential or ATP production). The results suggest that an underlying mechanism of organophosphate-based deficits in cognitive function might involve alterations in mitochondrial dynamics and/or their transport in axons.

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“…At high doses, neuronal apoptosis and oxidative stress are wellestablished consequences of CPF exposure, both in vitro and in vivo [9,18,23,42,51,76,82,93]. Adult animals treated with systemically toxic doses of sarin show major changes in the expression of apoptosis-related genes [28].…”

Section: Cpf and Dzn Cytotoxicitymentioning

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

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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Is oxidative stress involved in the developmental neurotoxicity of chlorpyrifos?

Cited by 119 publications

References 39 publications

Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period?

Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period?

Effects of Chlorpyrifos and Chlorpyrifos-Oxon on the Dynamics and Movement of Mitochondria in Rat Cortical Neurons

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

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