Prenatal chlorpyrifos exposure in rats causes persistent behavioral alterations

Levin, Edward D.; Addy, Nii A.; Baruah, Avanti; Elias, Alana; Christopher, N. Channelle; Seidler, Frederic J.; Slotkin, Theodore A.

doi:10.1016/s0892-0362(02)00272-6

Cited by 217 publications

(245 citation statements)

References 28 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%

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%

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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“…A similar phenomenon has been noted for effects on biomarkers of synaptic development (Qiao et al , 2003 and for behavioral consequences of gestational or neonatal CPF treatment (Levin et al 2001(Levin et al , 2002Icenogle et al In Press). Cholinergic input provides a positive trophic effect on brain development at the levels of cell maturation and regional architecture (Hohmann and Berger-Sweeney 1998;Lauder and Schambra 1999), and it is thus possible that raising the dose of CPF above the threshold for cholinesterase inhibition can partially offset deleterious effects mediated by noncholinergic mechanisms.…”

Section: Discussionsupporting

confidence: 57%

“…In the present study, we did not examine male and female fetuses separately. However, in previous work we found that CPF treatment on GD17-20 produces sex-dependent neurobehavioral differences that emerge in adolescence and adulthood (Levin et al 2002). If sexual differentiation is a component of CPF's targeted effects on brain development, then we would predict that the effects of earlier exposure on GD9-12 might not show sex dependence; these studies are currently under way.…”

Section: Discussionmentioning

confidence: 84%

“…In both periods, CPF elicits mitotic abnormalities, apoptosis, and architectural anomalies in the developing brain at exposures that are not otherwise embryotoxic Roy et al 1998;White et al 2002). At lower exposure levels, CPF-induced damage is not immediately apparent, but synaptic and functional abnormalities appear later, in adolescence and adulthood (Levin et al 2002;Qiao et al 2002Qiao et al , 2003. Thus, if the production of cAMP is involved in the adverse effects of CPF on brain development, effects on the AC signaling pathway should be evident immediately upon exposure to these lower exposures, preceding the delayed-onset anomalies.…”

mentioning

confidence: 99%

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Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: when is adenylyl cyclase a target?

Meyer

Seidler

Cousins

et al. 2003

Environ Health Perspect

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The developmental neurotoxicity of chlorpyrifos (CPF) involves mechanisms over and above cholinesterase inhibition. In the present study, we evaluated the effects of gestational CPF exposure on the adenylyl cyclase (AC) signaling cascade, which regulates the production of cyclic AMP, a major controller of cell replication and differentiation. In addition to basal AC activity, we assessed the AC response to direct enzymatic stimulants [forskolin, manganese (Mn 2+ )]; the response to isoproterenol, which activates signaling through β-adrenoceptors (βARs); and the concentration of βAR binding sites. CPF administered to pregnant rats on gestational days (GD) 9-12 elicited little or no change in any components of AC activity or βARs. However, shifting the treatment window to GD17-20 produced regionally selective augmentation of AC activity. In the brainstem, the response to forskolin or Mn 2+ was markedly stimulated by doses at or below the threshold for observable toxicity of CPF or for inhibition of fetal brain cholinesterase, whereas comparable effects were seen in the forebrain only at higher doses. In addition, low doses of CPF reduced βAR binding without impairing receptor-mediated stimulation of AC. These results indicate that signal transduction through the AC cascade is a target for CPF during a discrete developmental period in late gestation, an effect that is likely to contribute to the noncholinergic component of CPF's developmental neurotoxicity. Key words: adenylyl cyclase, β-adrenoceptor, brain development, chlorpyrifos, organophosphate insecticides.

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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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Prenatal chlorpyrifos exposure in rats causes persistent behavioral alterations

Cited by 217 publications

References 28 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

Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: when is adenylyl cyclase a target?

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

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