Persistent behavioral consequences of neonatal chlorpyrifos exposure in rats

Levin, Edward D.; Addy, Nii A.; Nakajima, Aya; Christopher, N. Channelle; Seidler, Frederic J.; Slotkin, Theodore A.

doi:10.1016/s0165-3806(01)00215-2

Cited by 208 publications

(260 citation statements)

References 21 publications

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“…The major effect shared by both CPF and DZN was a suppression of the development of ACh systems and promotion of monoamine systems, results at the transcriptional level that confirm earlier work on the switching of neuronal phenotype as a final outcome [4][5][6]25,49]. A change in transmitter phenotype is likely to produce "miswiring" of major brain circuits, where presynaptic neurons of one phenotype are juxtaposed to postsynaptic cells containing the incorrect complement of receptors and signaling pathways, effects that have already been noted as a final outcome for both ACh and 5HT systems [3,4,48,59,60]. Superimposed on these alterations, we found specific targeting of nAChR subtypes, a likely consequence of direct interaction of organophosphates with these ion channel receptors, as well as prominent effects on the receptors for the various monoamine neurotransmitters.…”

Section: General Conclusionsupporting

confidence: 80%

“…There are numerous studies showing significant sex differences in the pathways analyzed in our study and in the responses of these pathways to organophosphate exposure [3,6,26,60,79,89,90,94,96], and there is every reason to believe that transcriptional profiles will similarly exhibit major disparities between effects on males on females. This is obviously a subject for future study.…”

Section: Discussion Strategic Issues and Limitationsmentioning

confidence: 88%

“…Earlier work both in vivo and in vitro suggests that one of the main adverse effects of CPF on brain development is to produce inappropriate switching of the neurotransmitter phenotype, away from ACh and toward the monoamines [4][5][6]25,49]. Thus, whereas neonatal CPF exposure produces a deficit in hippocampal ACh innervation and activity, 5HT systems then take over the corresponding neurobehavioral functions [3,60]. Accordingly, we found consistent increases in the genes responsible for monoamine synthesis and storage, entirely in keeping with this phenotypic switch.…”

Section: Cpf and Dzn Effects On Neurotransmitter Systemsmentioning

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: General Conclusionsupporting

confidence: 80%

Section: Discussion Strategic Issues and Limitationsmentioning

confidence: 88%

Section: Cpf and Dzn Effects On Neurotransmitter Systemsmentioning

confidence: 99%

See 1 more Smart Citation

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

show abstract

“…First, for the in vivo studies, we restricted our analysis to males, primarily because of limited technical and financial considerations. Certainly, the developmental neurotoxicity or organophosphates is known to have important sex-selective components [2,48,64,73,74,78,80], and it is likely that transcriptional profiles will similarly exhibit major sex disparities, a subject for future study. Similarly, the PC12 model does not permit distinction of effects that interact with sex, a clear limitation of comparing in vitro to in vivo findings.…”

Section: Discussionmentioning

confidence: 99%

Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro

Slotkin¹,

Seidler²,

Fumagalli³

2008

Brain Research Bulletin

127

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Neurotrophic factors control neural cell differentiation and assembly of neural circuits. We previously showed that organophosphate pesticides differentially regulate members of the fibroblast growth factor (fgf) gene family. We administered chlorpyrifos and diazinon to neonatal rats on postnatal days 1-4 at doses devoid of systemic toxicity or growth impairment, and spanning the threshold for barely-detectable cholinesterase inhibition. We evaluated the impact on gene families for different classes of neurotrophic factors. Using microarrays, we examined the regional expression of mRNAs encoding the neurotrophins (ntfs), brain-derived neurotrophic factor (bdnf), nerve growth factor (ngf), the wnt and fzd gene families and the corresponding receptors. Chlorpyrifos and diazinon both had widespread effects on the fgf, ntf, wnt and fzd families but much less on the bdnf and ngf groups. However, the two organophosphates showed disparate effects on a number of key neurotrophic factors. To determine if the actions were mediated directly on differentiating neurons, we tested chlorpyrifos in PC12 cells, an in vitro model of neural cell development. Effects in PC12 cells mirrored many of those for members of the fgf, ntf and wnt families, as well as the receptors for the ntfs, especially during early differentiation, the stage known to be most susceptible to disruption by organophosphates. Our results suggest that actions on neurotrophic factors provide a mechanism for the developmental neurotoxicity of low doses of organophosphates, and, since effects on expression of the affected genes differed with test agent, may help explain regional disparities in effects and critical periods of vulnerability.

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“…In particular, heroin-induced deficits in eight arm and Morris maze behaviors. [16][17][18][19][20][21][39][40][41] Both of these behavioral tests are affected by the cholinergic septohippocampal projection. [42][43][44] On the biochemical/molecular level, prenatal heroin induced both pre-and postsynaptic hyperactivity in the hippocampal cholinergic innervation, 16,17,23,45 converging on a total abolishment of the specific cholinergic-induced activation of PKCg.…”

Section: Discussionmentioning

confidence: 99%

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

2007

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Grafting of neural progenitors has been shown to reverse a wide variety of neurobehavioral defects. While their role of replacing injured cells and restoring damaged circuitries has been shown, it is widely accepted that this cannot be the only mechanism, as therapy can occur even when an insufficient number of transplanted cells are found. We hypothesized that one major mechanism by which transplanted neural progenitors exert their therapeutic effect is by enhancing endogenous cells production. Consequently, in an allographic model of transplantation, prenatally heroin-exposed genetically heterogeneous (HS) mice were made defective in their hippocampal neurobehavioral function by exposing their mothers to heroin (10 mg kg À1 heroin on gestation days 9-18). Hippocampal damage was confirmed by deficient performance in the Morris maze (P < 0.009), and decreased production of endogenous cells in the dentate gyrus by 39% was observed. On postnatal day 35, they received an HS-derived neural progenitors transplant followed by repeated bromodeoxyuridine injections. The transplant returned endogenous cells production to normal levels (P < 0.006) and reversed the behavioral defects (P < 0.03), despite the fact that only 0.0334% of the transplanted neural progenitors survived and that they differentiated mainly to astrocytes. An immunological study demonstrated the presence of macrophages and T cells as a possible explanation for the paucity of the transplanted cells. This study suggests one mechanism for the therapeutic action of neural progenitors, the enhancement of the production of endogenous cells, pointing to future clinical applications in this direction by use of neural progenitors or by analogous cell-inducing techniques.

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Persistent behavioral consequences of neonatal chlorpyrifos exposure in rats

Cited by 208 publications

References 21 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

Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

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